Publications by authors named "Saye H Khoo"

100 Publications

Pharmacokinetic interactions of modern antiretroviral therapy.

AIDS 2021 Dec;35(Suppl 2):S145-S151

Chelsea and Westminster Hospital.

Drug--drug interactions (DDIs) have been a clinical challenge in HIV medicine for over two decades. The newer antiretroviral drugs (ARTs) have significantly fewer DDIs than protease inhibitors and boosted integrase inhibitors (INSTIs). The lower propensity of such newer antiretrovirals (e.g. unboosted integrase inhibitors; doravirine) to cause DDIs, has been largely offset by the ageing cohort of patients with multiple comorbidities, who are taking multiple chronic medicines. Furthermore, the introduction of newly marketed drugs into clinical practice needs to be closely monitored, as the new drugs may be perpetrators of DDIs, leading to a potential change in the efficacy or toxicity of the coadministered antiretrovirals.
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http://dx.doi.org/10.1097/QAD.0000000000002950DOI Listing
December 2021

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

J Antimicrob Chemother 2021 11;76(12):3286-3295

Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK.

Objectives: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection.

Methods: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses.

Results: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%.

Conclusions: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.
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http://dx.doi.org/10.1093/jac/dkab318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598307PMC
November 2021

Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance?

J Antimicrob Chemother 2021 08;76(9):2230-2233

Department of Pharmacology and Therapeutics, Materials Innovation Factory, University of Liverpool, Liverpool, L7 3NY, UK.

This article provides a brief overview of drug resistance to antiviral therapy as well as known and emergent variability in key SARS-CoV-2 viral sequences. The purpose is to stimulate deliberation about the need to consider drug resistance prior to widespread roll-out of antivirals for SARS-CoV-2. Many existing candidate agents have mechanisms of action involving drug targets likely to be critical for future drug development. Resistance emerged quickly with monotherapies deployed for other pulmonary viruses such as influenza virus, and in HIV mutations in key drug targets compromised efficacy of multiple drugs within a class. The potential for drug resistance in SARS-CoV-2 has not yet been rigorously debated or assessed, and we call for more academic and industry research on this potentially important future threat prior to widespread roll-out of monotherapies for COVID-19 treatment and prevention.
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http://dx.doi.org/10.1093/jac/dkab189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361339PMC
August 2021

Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria.

AIDS 2021 10;35(12):1919-1927

Department of Pharmaceutical Chemistry.

Objective: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance.

Design: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected.

Methods: Participants (N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography-tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning.

Results: Strong correlation (r = 0.66, P < 0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85 ng/mg (4.56-10.93). CYP2B6 516G>T, (P < 0.001) and CYP2B6 983T>C (P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (P < 0.001) and 983T>C (P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (r = 0.23, P = 0.043) and 983T>C genotype (r = 0.38, P < 0.0005).

Conclusion: This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.
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http://dx.doi.org/10.1097/QAD.0000000000002984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462442PMC
October 2021

Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5'-triphosphate exposure to support posology for SARS-CoV-2.

J Antimicrob Chemother 2021 07;76(8):2121-2128

Department of Pharmacology and Therapeutics, Materials Innovation Factory, University of Liverpool, Liverpool L7 3NY, UK.

Objectives: Favipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5'-triphosphate (FAVI-RTP)].

Methods: Published in vitro data for intracellular production and elimination of FAVI-RTP in Madin-Darby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions.

Results: Parameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of ∼1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of ∼2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life.

Conclusions: Population mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9 days with a 1200 mg twice-daily regimen (following a 1600 mg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.
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http://dx.doi.org/10.1093/jac/dkab135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194902PMC
July 2021

Pharmacokinetics and Drug-Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine.

Clin Pharmacokinet 2021 07 8;60(7):835-853. Epub 2021 Apr 8.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Combined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection, thus transforming HIV infection into a chronic disease; however, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. A major milestone in HIV treatment is the marketing of the long-acting intramuscular antiretroviral drugs cabotegravir and rilpivirine, allowing for infrequent drug administration, with the potential to improve adherence to therapy and treatment satisfaction. Intramuscular administration of cabotegravir and rilpivirine leads to differences in pharmacokinetics and drug-drug interaction (DDI) profiles compared with oral administration. A notable difference is the long elimination half-life with intramuscular administration, which reaches 5.6-11.5 weeks for cabotegravir and 13-28 weeks for rilpivirine, compared with 41 and 45 h, respectively, with their oral administration. Cabotegravir and rilpivirine have a low potential to cause DDIs, however these drugs can be victims of DDIs. Cabotegravir is mainly metabolized by UGT1A1, and rilpivirine is mainly metabolized by CYP3A4, therefore these agents are susceptible to DDIs with inhibitors, and particularly inducers of drug-metabolizing enzymes. Intramuscular administration of cabotegravir and rilpivirine has the advantage of eliminating DDIs occurring at the gastrointestinal level, however interactions can still occur at the hepatic level. This review provides insight on the intramuscular administration of drugs and summarizes the pharmacology of long-acting cabotegravir and rilpivirine. Particular emphasis is placed on DDI profiles after oral and intramuscular administration of these antiretroviral drugs.
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http://dx.doi.org/10.1007/s40262-021-01005-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249281PMC
July 2021

Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5'-triphosphate exposure to support posology for SARS-CoV-2.

medRxiv 2021 Jan 5. Epub 2021 Jan 5.

Background: The role of favipiravir as a treatment for COVID-19 is unclear, with discrepant activity against SARS-CoV-2 , concerns about teratogenicity and pill burden, and an unknown optimal dose. In Vero-E6 cells, high concentrations are needed to inhibit SARS-CoV-2 replication. The purpose of this analysis was to use available data to simulate intracellular pharmacokinetics of favipiravir ribofuranosyl-5⍰-triphosphate (FAVI-RTP) to better understand the putative applicability as a COVID-19 intervention.

Methods: Previously published data for the intracellular production and elimination of FAVI- RTP in MDCK cells incubated with parent favipiravir was fitted with a mathematical model to describe the time course of intracellular FAVI-RTP concentrations as a function of incubation concentration of parent favipiravir. Parameter estimates from this model fitting were then combined with a previously published population PK model for the plasma exposure of parent favipiravir in Chinese patients with severe influenza (the modelled free plasma concentration of favipiravir substituting for incubation concentration) to predict the human intracellular FAVI-RTP pharmacokinetics.

Results: FAVI-RTP data was adequately described as a function of incubation media concentrations of parent favipiravir with an empirical model, noting that the model simplifies and consolidates various processes and is used under various assumptions and within certain limits. Parameter estimates from the fittings to data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP when driven by a predicted free plasma concentration profile.

Conclusion: This modelling approach has several important limitations that are discussed in the main text of the manuscript. However, the simulations indicate that despite rapid clearance of the parent drug from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. Population average intracellular FAVI-RTP concentrations are estimated to maintain the Km for the SARS-CoV-2 polymerase for 3 days following 800 mg BID dosing and 9 days following 1200 mg BID dosing after a 1600 mg BID loading dose on day 1. Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.
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http://dx.doi.org/10.1101/2021.01.03.21249159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805475PMC
January 2021

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

Br J Clin Pharmacol 2021 04 1;87(4):2078-2088. Epub 2020 Dec 1.

Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC .

Methods: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.

Results: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated.

Conclusion: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
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http://dx.doi.org/10.1111/bcp.14619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056737PMC
April 2021

Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis.

Clin Infect Dis 2021 11;73(9):e3365-e3373

Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

Background: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis.

Methods: Malawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.

Results: One-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2-18.0-fold) and 49.8-fold (95% CI, 34.2-65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell-plasma ratio, 15.0; 95% CI, 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response.

Conclusions: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.
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http://dx.doi.org/10.1093/cid/ciaa1265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563277PMC
November 2021

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Open Forum Infect Dis 2020 Jul 6;7(7):ofaa218. Epub 2020 Jun 6.

Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

Background: This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.

Methods: Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing.

Results: Higher isoniazid exposure correlated with increased bacillary killing in sputum (.01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC) (01). Serial sputum colony counting negativity at month 2 (05), isoniazid (.05), isoniazid /minimum inhibitory concentration ([MIC] 01), and isoniazid AUC/MIC (01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (05) and earlier progression to biphasic bacillary decline (01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (05).

Conclusions: Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as /MIC and AUC/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.
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http://dx.doi.org/10.1093/ofid/ofaa218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378673PMC
July 2020

Safety perspectives on presently considered drugs for the treatment of COVID-19.

Br J Pharmacol 2020 10 13;177(19):4353-4374. Epub 2020 Aug 13.

MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.

Intense efforts are underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm-benefit ratios that may be encountered when treating COVID-19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life-threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID-19.
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http://dx.doi.org/10.1111/bph.15204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404855PMC
October 2020

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

medRxiv 2020 May 6. Epub 2020 May 6.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organisation and urgent treatment and prevention strategies are needed. Many clinical trials have been initiated with existing medications, but assessments of the expected plasma and lung exposures at the selected doses have not featured in the prioritisation process. Although no antiviral data is currently available for the major phenolic circulating metabolite of nitazoxanide (known as tizoxanide), the parent ester drug has been shown to exhibit activity against SARS-CoV-2. Nitazoxanide is an anthelmintic drug and its metabolite tizoxanide has been described to have broad antiviral activity against influenza and other coronaviruses. The present study used physiologically-based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported nitazoxanide 90% effective concentration (EC ) against SARS-CoV-2.

Methods: A whole-body PBPK model was constructed for oral administration of nitazoxanide and validated against available tizoxanide pharmacokinetic data for healthy individuals receiving single doses between 500 mg SARS-CoV-2 4000 mg with and without food. Additional validation against multiple-dose pharmacokinetic data when given with food was conducted. The validated model was then used to predict alternative doses expected to maintain tizoxanide plasma and lung concentrations over the reported nitazoxanide EC in >90% of the simulated population. Optimal design software PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.

Results: The PBPK model was validated with AAFE values between 1.01 SARS-CoV-2 1.58 and a difference less than 2-fold between observed and simulated values for all the reported clinical doses. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food, to provide tizoxanide plasma and lung concentrations over the reported EC of nitazoxanide against SARS-CoV-2. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated.

Conclusion: The PBPK model predicted that it was possible to achieve plasma and lung tizoxanide concentrations, using proven safe doses of nitazoxanide, that exceed the EC for SARS-CoV-2. The PBPK model describing tizoxanide plasma pharmacokinetics after oral administration of nitazoxanide was successfully validated against clinical data. This dose prediction assumes that the tizoxanide metabolite has activity against SARS-CoV-2 similar to that reported for nitazoxanide, as has been reported for other viruses. The model and the reported dosing strategies provide a rational basis for the design (optimising plasma and lung exposures) of future clinical trials of nitazoxanide in the treatment or prevention of SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.05.01.20087130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274229PMC
May 2020

Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.

Clin Pharmacol Ther 2020 10 14;108(4):775-790. Epub 2020 Jun 14.

Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (C ) at an approved dose in humans (C /EC ratio). Only 14 of the 56 analyzed drugs achieved a C /EC ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (K U ) was also simulated to derive a lung C /half-maximal effective concentration (EC ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC . Nitazoxanide and sulfadoxine also exceeded their reported EC by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.
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http://dx.doi.org/10.1002/cpt.1909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280633PMC
October 2020

An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.
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http://dx.doi.org/10.1128/AAC.02394-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179577PMC
April 2020

Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: an open label non-randomized interventional trial.

Malar J 2019 Aug 20;18(1):277. Epub 2019 Aug 20.

University of Malawi, College of Medicine, Blantyre, Malawi.

Background: HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Dihydroartemisinin-piperaquine (DPQ) is recommended for treatment of Plasmodium falciparum malaria, but its efficacy and safety has not been evaluated in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events were assessed in HIV-infected individuals on non-nucleoside reverse transcriptase inhibitor-based ART (efavirenz and nevirapine) with uncomplicated P. falciparum malaria treated with dihydroartemisinin-piperaquine.

Methods: An open label single arm clinical trial was conducted in Malawi (Blantyre and Chikhwawa districts) and Mozambique (Manhiça district) involving patients aged 15-65 years with uncomplicated P. falciparum malaria who were on efavirenz-based or nevirapine-based ART. They received a directly-observed 3-day standard treatment of DPQ and were followed up until day 63 for malaria infection and adverse events. Day-42 PCR-corrected-ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat (ITT) population.

Results: The study enrolled 160 and 61 patients on efavirenz and nevirapine-based ART, with a baseline geometric mean (95% CI) parasite density of 2681 (1964-3661) and 9819 (6606-14,593) parasites/µL, respectively. The day-42 PCR-corrected ACPR (95% CI) was 99.4% (95.6-99.9%) in the efavirenz group and 100% in the nevirapine group. Serious adverse events occurred in 5.0% (8/160) and 3.3% (2/61) of the participants in the efavirenz and nevirapine group, respectively, but none were definitively attributable to DPQ. Cases of prolonged QT interval (> 60 ms from baseline) occurred in 31.2% (48/154) and 13.3% (8/60) of the patients on the efavirenz and nevirapine ART groups, respectively. These were not clinically significant and resolved spontaneously over time. As this study was not designed to compare the efficacy and safety of DPQ in the two ART groups, no formal statistical comparisons were made between the two ART groups.

Conclusions: DPQ was highly efficacious and safe for the treatment of malaria in HIV-infected patients concurrently taking efavirenz- or nevirapine-based ART, despite known pharmacokinetic interactions between dihydroartemisinin-piperaquine and efavirenz- or nevirapine-based ART regimens. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013, https://pactr.samrc.ac.za/Search.aspx.
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http://dx.doi.org/10.1186/s12936-019-2909-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700797PMC
August 2019

Efficacy and safety of artemether-lumefantrine as treatment for Plasmodium falciparum uncomplicated malaria in adult patients on efavirenz-based antiretroviral therapy in Zambia: an open label non-randomized interventional trial.

Malar J 2019 May 24;18(1):180. Epub 2019 May 24.

University of Malawi, College of Medicine, Blantyre, Malawi.

Background: HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Artemether-lumefantrine (AL) is the most commonly used ACT for treatment of falciparum malaria in Africa but there is limited evidence on the safety and efficacy of AL in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events was assessed in HIV-infected individuals on efavirenz-based ART with uncomplicated falciparum malaria treated with AL.

Methods: A prospective, open label, non-randomized, interventional clinical trial was conducted at St Paul's Hospital in northern Zambia, involving 152 patients aged 15-65 years with uncomplicated falciparum malaria, who were on efavirenz-based ART. They received a 3-day directly observed standard treatment of AL and were followed up until day 63. Day-42 polymerase chain reaction (PCR)-corrected ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat population.

Results: Enrolled patients had a baseline geometric mean (95% CI) parasite density of 1108 (841-1463) parasites/µL; 16.4% (25/152) of the participants had a recurrent malaria episode by day 42. However, PCR data was available for 17 out of the 25 patients who had malaria recurrence. Among all the 17 patients, PCR findings demonstrated malaria re-infection, making the PCR-adjusted day-42 ACPR 100% in the 144 patients who could be evaluated. Even when eight patients with missing PCR data were considered very conservatively as failures, the day-42 ACPR was over 94%. None of the participants, disease or treatment characteristics, including day-7 lumefantrine concentrations, predicted the risk of malaria recurrence by day 42. AL was well tolerated following administration. There were only two cases of grade 3 neutropaenia and one serious adverse event of lobar pneumonia, none of which was judged as probably related to intake of AL.

Conclusions: AL was well tolerated and efficacious in treating uncomplicated falciparum malaria in HIV co-infected adults on efavirenz-based ART. However, a higher than anticipated proportion of participants experienced malaria re-infection, which highlights the need for additional malaria prevention measures in this sub-population after treatment with AL. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013. https://pactr.samrc.ac.za/Search.aspx.
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http://dx.doi.org/10.1186/s12936-019-2818-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534937PMC
May 2019

Carbamazepine intervention in a patient with efavirenz-induced liver injury.

AIDS 2019 05;33(6):1097-1098

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1097/QAD.0000000000002116DOI Listing
May 2019

Therapeutic drug monitoring of darunavir/ritonavir in pregnancy.

Antivir Ther 2019 ;24(3):229-233

School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.

Background: Physiological changes during pregnancy can have a significant impact on antiretroviral pharmacokinetics (PK), which may result in reduced drug efficacy. Here we describe the PK of darunavir/ritonavir (DRV/r) 800/100 once daily in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM) as well as transplacental passage of DRV by measuring and comparing cord blood and maternal blood samples at delivery.

Methods: Pregnant HIV-positive women received DRV/r as part of routine pre-natal care. Demographic and clinical data were collected. DRV plasma concentrations [DRV] were determined in the first (T1), second (T2) and third (T3) trimester and at postpartum (PP). The target concentration was 550 ng/ml. Where possible, paired maternal and cord blood samples were taken at delivery.

Results: A total of 33 women were enrolled. Samples were taken 14-20 h post-dose and measured concentrations were extrapolated to 24 h post-dose. At the time nearest to delivery, all but four had undetectable plasma viral loads (pVL). [DRV] were determined in 1 (T1); 14 (T2); 32 (T3) and 29 (PP). 1 sample was <550 ng/ml at T2, 6 at T3 and 3 at PP. [DRV] were significantly lower at T2/T3 relative to PP.

Conclusions: [DRV] in T2 and T3 were 36-55% when compared with PP. However, DRV PK in pregnancy were not associated with a lack of virological suppression at delivery as of the 33 patients enrolled in this study, 31 had no HIV transmission from mother to child. Data regarding two candidates were not available as they delivered in a separate health-care facility.
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http://dx.doi.org/10.3851/IMP3291DOI Listing
May 2020

Widespread use of herbal medicines by people living with human immunodeficiency virus and contamination of herbal medicines with antiretrovirals in Nigeria.

Int J STD AIDS 2019 03 30;30(4):371-377. Epub 2018 Nov 30.

1 Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Herbal medication use amongst people living with human immunodeficiency virus (PLWH) is widespread and understudied. This study aimed to evaluate the prevalence of herbal medicine use amongst PLWH and possible contamination with antiretrovirals (ARVs). Countrywide collection of herbal samples sold by street vendors in Nigeria for the following indications: human immunodeficiency virus (HIV), acquired immune deficiency syndrome, fever and general weakness. Samples were screened using a validated liquid chromatography-mass spectrometry/mass spectrometry method for the presence of the following ARVs: efavirenz, nevirapine, lopinavir, darunavir, ritonavir, atazanavir, emtricitabine, tenofovir and lamivudine. A survey was conducted among 742 PLWH attending four HIV clinics in Nigeria. Data were collected using a structured questionnaire and analysed using IBM SPSS statistics version 22.0 (IBM Corp., 2013, Armond, NY). Of the 138 herbal medicines sampled, three (2%) contained detectable levels of tenofovir, emtricitabine and/or lamivudine. Additionally, of the 742 PLWH surveyed, 310 (41.8%) reported herbal medicine use. Among the users, 191 (61.6%) started taking herbals after commencing HIV therapy while herbal medicine use preceded ARVs treatment in 119 (38.4%) PLWH. We found herbal use to be widespread among PLWH in Nigeria, with increasing use after commencing ARV. Three herbal preparations were also found to contain detectable levels of ARVs. This is a concern and should be studied widely across the region and countries where herbal medicine use is prevalent and poorly regulated.
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http://dx.doi.org/10.1177/0956462418809749DOI Listing
March 2019

Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine.

Antimicrob Agents Chemother 2019 02 29;63(2). Epub 2019 Jan 29.

Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.).
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http://dx.doi.org/10.1128/AAC.01310-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355558PMC
February 2019

Impact of Efavirenz-, Ritonavir-Boosted Lopinavir-, and Nevirapine-Based Antiretroviral Regimens on the Pharmacokinetics of Lumefantrine and Safety of Artemether-Lumefantrine in Plasmodium falciparum-Negative HIV-Infected Malawian Adults Stabilized on Antiretroviral Therapy.

Antimicrob Agents Chemother 2018 11 24;62(11). Epub 2018 Oct 24.

University of Malawi, College of Medicine, Blantyre, Malawi

There is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and the safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve from 0 h to 14 days (AUC) of lumefantrine and the safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV)-infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups ( = 6/group): (i) antiretroviral naive, (ii) nevirapine-based ART, (iii) efavirenz-based ART, and (iv) ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups ( = 10 to 15/group): (i) antiretroviral naive, (ii) efavirenz-based ART, and (iii) ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine's AUC was 53% (95% confidence interval [CI], 0.27 to 0.82) lower in the efavirenz-based ART group than in the ART-naive group and was 2.4 (95% CI, 1.58 to 3.62) and 2.9(95% CI, 1.75 to 4.72) times higher in the nevirapine- and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine's AUC was 1.9 (95% CI, 1.26 to 3.00) times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz- and ART-naive groups (0.99 [95% CI, 0.63 to 1.57]). Frequent cases of hematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria-coinfected adults. (This study has been registered at the Pan African Clinical Trials Registry under numbers PACTR2010030001871293 and PACTR2010030001971409.).
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http://dx.doi.org/10.1128/AAC.01162-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201074PMC
November 2018

Pharmacokinetics of Piperaquine and Safety Profile of Dihydroartemisinin-Piperaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

Antimicrob Agents Chemother 2018 08 27;62(8). Epub 2018 Jul 27.

Malawi College of Medicine, Blantyre, Malawi

There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus-infected (HIV-positive [HIV]) individuals taking antiretroviral therapy (ART). In a two-step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared the area under the concentration-time curve from days 0 to 28 (AUC) and the safety outcomes of piperaquine among malaria-uninfected HIV adults. In step 1, half the adult dose of DHA-PQ was administered for 3 days as an initial safety check to four groups ( = 6/group) of HIV adults (age ≥18 years): (i) antiretroviral-naive individuals, (ii) individuals on nevirapine-based ART, (iii) individuals on efavirenz-based ART, and (iv) individuals on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral-naive individuals, (ii) individuals on efavirenz-based ART, and (iii) individuals on nevirapine-based ART ( = 10 to 15/group). The ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to the limited number of participants who were on this second-line ART and were eligible for recruitment. Piperaquine's AUC in both steps was 43% lower among participants on efavirenz-based ART than among ART-naive participants. There were no significant differences in AUC between the other ART groups and the ART-naive group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although it was well tolerated at the half and full standard adult treatment courses, the efavirenz-based antiretroviral regimen was associated with reduced piperaquine exposure, which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings. (The clinical trials presented in this study have been registered at the WHO's International Clinical Trials Registry Platform under ID numbers PACTR2010030001871293 and PACTR2010030001971409.).
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http://dx.doi.org/10.1128/AAC.00634-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105794PMC
August 2018

Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

Antimicrob Agents Chemother 2018 07 26;62(7). Epub 2018 Jun 26.

Malawi College of Medicine, Blantyre, Malawi

There are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus-infected (HIV) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults ( = 6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort ( = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC, with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng · h/ml ( < 0.001). No significant differences in AUC were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity.
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http://dx.doi.org/10.1128/AAC.00412-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021620PMC
July 2018

Development, validation and utilization of a highly sensitive LC-MS/MS method for quantification of levonorgestrel released from a subdermal implant in human plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 May 12;1084:106-112. Epub 2018 Mar 12.

Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. Electronic address:

Levonorgestrel (LNG) is a synthetic progestin that is available in oral contraceptive tablets, a subdermal implant, and an intrauterine system for contraception. LNG pharmacokinetics are a pivotal determinant of contraceptive efficacy and essential in assessing drug-drug interactions influencing LNG exposure following different routes of LNG administration. A highly sensitive LC-MS/MS method was developed and validated to quantify levonorgestrel in human plasma. Liquid-liquid extraction was utilized with a sample volume of 500 μL to extract levonorgestrel from plasma. Chromatographic separation of LNG was achieved with a Fortis™ C18 (3 μm: 100 mm × 2.1 mm) reverse phase analytical column. The mobile phases consisted of de-ionized water plus 0.1% NHOH (100:0.1%, v/v) (A), and methanol plus 0.1% NHOH (100:0.1%, v/v) (B) delivered as a gradient at a flow rate of 400 μL/min. Detection of LNG and internal standard (D-(-)-norgestrel-d7) was achieved using positive polarity mode monitoring at 313.2-245.2 amu and 320.1-251.2 amu, respectively. The assay was linear over the calibration range of 49.6 to 1500 pg/mL. This method was used to quantify plasma LNG released by subdermal implant in support of a drug interaction study among women with HIV receiving efavirenz- or nevirapine-based antiretroviral therapy.
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http://dx.doi.org/10.1016/j.jchromb.2018.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892837PMC
May 2018

Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

Antimicrob Agents Chemother 2017 07 27;61(7). Epub 2017 Jun 27.

Royal Liverpool University Hospital, Liverpool, United Kingdom

Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in and other candidate genes ( and ) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in did not explain variability in AUC of rifampin. No pharmacokinetic associations were identified with or SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.
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http://dx.doi.org/10.1128/AAC.00210-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487625PMC
July 2017

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection.

PLoS One 2017 23;12(3):e0173509. Epub 2017 Mar 23.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

Background: In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria.

Methods And Findings: This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs.

Conclusions: There is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of recommendation criteria to DDI data is feasible, and allows the assessment of DDIs to be robust, consistent, transparent and evidence-based.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173509PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363796PMC
August 2017

Impact of polypharmacy on antiretroviral prescription in people living with HIV.

J Antimicrob Chemother 2017 02 9;72(2):511-514. Epub 2016 Nov 9.

Institute of Translational Medicine, University of Liverpool & Royal Liverpool University Hospital, Liverpool, UK.

Objectives: To evaluate the relationship between polypharmacy and ART, delivered as conventional multi-tablet three-drug regimens, single-tablet regimens or less-drug regimens (simplified mono or dual regimens).

Methods: We conducted a cross-sectional analysis of electronic data from the prospective Modena HIV Metabolic Clinic Cohort Study. We included the last clinical observation for each patient from January 2006 to December 2015. Polypharmacy was defined as the use of five or more medications (excluding ART). Multi-morbidity was classified as the presence of two or more non-infectious comorbidities. Factors associated with different ART regimens were analysed using multivariable multinomial logistic regression analyses with multi-tablet three-drug regimens as the reference.

Results: A total of 2944 patients (33.7% females) were included in the analysis. Multinomial logistic regression analysis identified polypharmacy to be negatively associated with single-tablet regimens [relative risk reduction (RRR) = 0.48, 95% CI = 0.28-0.81] independently from frailty (RRR = 0.68, 95% CI = 0.59-0.78), after correction for age, gender, HIV infection duration, current and nadir CD4 and calendar year. This association was not found comparing multi-tablet three-drug regimens and less-drug regimens.

Conclusions: Single-tablet regimens are less likely to be prescribed in patients with polypharmacy. Single-tablet regimens are perceived to be less flexible in patients with multi-morbidity and at higher risk of drug-drug interaction.
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http://dx.doi.org/10.1093/jac/dkw437DOI Listing
February 2017

Perceptions of Research Bronchoscopy in Malawian Adults with Pulmonary Tuberculosis: A Cross-Sectional Study.

PLoS One 2016 28;11(10):e0165734. Epub 2016 Oct 28.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

Bronchoscopy is an established research tool in Malawi, enabling collection of pulmonary samples for immunological, pharmacological, and microbiological studies. It is, however, an invasive clinical procedure that offers no direct benefit to volunteering participants when used in a research capacity alone, and thus informed consent is essential. This study aimed to explore TB patients' understanding of research bronchoscopy, what would motivate them to participate in research bronchoscopy, and their concerns, in order to inform consenting processes for future clinical studies. We used a qualitative research design. Two focus group discussions were conducted with community members and TB patients to understand their perceptions of bronchoscopy. Transcripts were coded by multiple co-authors and thematic content analysis was used to analyse main findings. We found that Malawian patients with pulmonary TB were willing to participate in a study using research bronchoscopy for health assessment and access to improved healthcare. We identified information of value to potential participants when consenting to that may lessen some of the anxieties expressed by participants. Patient and public involvement is essential to improve informed consent and institutional trust.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165734PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085028PMC
June 2017

Adequacy of Rifampin Absorption after Jejunostomy Tube Administration.

Pharmacotherapy 2016 Apr 6;36(4):e23-5. Epub 2016 Apr 6.

Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high-pressure liquid chromatography demonstrated a peak serum rifampin level (C(max)) of 18 μg/ml and total rifampin exposure (area under the curve from 0-6 hours [AUC(0-6)]) of 50.1 μg/ml. These are high compared with rifampin C(max) and AUC(0-6) values reported in patients after oral rifampin administration; C(max) tends to range between 4.0-10.5 μg/ml and AUC(0-6) 7.0-52.9 μg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C(max) and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.
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http://dx.doi.org/10.1002/phar.1730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071684PMC
April 2016

First experience of effectiveness and safety of bedaquiline for 18 months within an optimised regimen for XDR-TB.

Eur Respir J 2016 05 25;47(5):1581-4. Epub 2016 Feb 25.

Liverpool School of Tropical Medicine, Liverpool, UK Liverpool Heart and Chest Hospital, Liverpool, UK.

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http://dx.doi.org/10.1183/13993003.01980-2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394548PMC
May 2016
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