Publications by authors named "Andrew W Harrell"

8 Publications

  • Page 1 of 1

A Novel Inhaled Dry-Powder Formulation of Ribavirin Allows for Efficient Lung Delivery in Healthy Participants and Those with Chronic Obstructive Pulmonary Disease in a Phase 1 Study.

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

GlaxoSmithKline, Collegeville, Pennsylvania, USA

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.).
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http://dx.doi.org/10.1128/AAC.02267-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179635PMC
April 2020

Drug Interactions for Low-Dose Inhaled Nemiralisib: A Case Study Integrating Modeling, In Vitro, and Clinical Investigations.

Drug Metab Dispos 2020 04 2;48(4):307-316. Epub 2020 Feb 2.

Drug Metabolism and Pharmacokinetics (A.P., A.W.H., K.S.T., M.T., H.T.) and Bioanalysis, Immunogenicity and Biomarkers (A.G.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences, GlaxoSmithKline R&D, Stevenage, United Kingdom (R.W.); Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Discovery Medicine, GlaxoSmithKline, Stevenage, United Kingdom (A.P.C.); Safety and Medical Governance, GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom (M.M.); and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.).

In vitro data for low-dose inhaled phosphoinositide 3-kinase delta inhibitor nemiralisib revealed that it was a substrate and a potent metabolism-dependent inhibitor of cytochrome P450 (P450) 3A4 and a P-glycoprotein (P-gp) substrate. An integrated in silico, in vitro, and clinical approach including a clinical drug interaction study as well as a bespoke physiologically based pharmacokinetic (PBPK) model was used to assess the drug-drug interaction (DDI) risk. Inhaled nemiralisib (100 µg, single dose) was coadministered with itraconazole, a potent P4503A4/P-gp inhibitor, following 200 mg daily administrations for 10 days in 20 male healthy subjects. Systemic exposure to nemiralisib (AUC) increased by 2.01-fold versus nemiralisib alone. To extrapolate the clinical data to other P4503A4 inhibitors, an inhaled PBPK model was developed using Simcyp software. Retrospective simulation of the victim risk showed good agreement between simulated and observed data (AUC ratio 2.3 vs. 2.01, respectively). Prospective DDI simulations predicted a weak but manageable drug interaction when nemiralisib was coadministered with other P4503A4 inhibitors, such as the macrolides clarithromycin and erythromycin (simulated AUC ratio of 1.7), both common comedications in the intended patient populations. PBPK and static mechanistic models were also used to predict a negligible perpetrator DDI effect for nemiralisib on other P4503A4 substrates, including midazolam (a sensitive probe substrate of P4503A4) and theophylline (a narrow therapeutic index drug and another common comedication). In summary, an integrated in silico, in vitro, and clinical approach including an inhalation PBPK model has successfully discharged any potential patient DDI risks in future nemiralisib clinical trials. SIGNIFICANCE STATEMENT: This paper describes the integration of in silico, in vitro, and clinical data to successfully discharge potential drug-drug interaction risks for a low-dose inhaled drug. This work featured assessment of victim and perpetrator risks of drug transporters and cytochrome P450 enzymes, utilizing empirical and mechanistic approaches combined with clinical data (drug interaction and human absorption, metabolism, and pharmacokinetics) and physiologically based pharmacokinetic modeling approaches to facilitate bespoke risk assessment in target patient populations.
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http://dx.doi.org/10.1124/dmd.119.089003DOI Listing
April 2020

An Innovative Approach to Characterize Clinical ADME and Pharmacokinetics of the Inhaled Drug Nemiralisib Using an Intravenous Microtracer Combined with an Inhaled Dose and an Oral Radiolabel Dose in Healthy Male Subjects.

Drug Metab Dispos 2019 12 24;47(12):1457-1468. Epub 2019 Oct 24.

Drug Metabolism and Pharmacokinetics (A.W.H., G.Y., R.C., D.K.) and Bioanalysis, Immunogenicity and Biomarkers (A.G., A.P.), GlaxoSmithKline R&D, Ware, United Kingdom; RD Projects Clinical Platforms & Sciences (R.W.), Drug Metabolism and Pharmacokinetics (C.B.), Discovery Medicine (Y.L.M.), Biostatistics (E.J.), GlaxoSmithKline R&D and Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (E.M.H.); Safety and Medical Governance (M.M.) and Discovery Medicine (W.A.F.), GlaxoSmithKline R&D, Stockley Park, Uxbridge, United Kingdom; Global Clinical and Data Operations, GlaxoSmithKline R&D, Ermington, Australia (K.R.); Covance Laboratories, Harrogate, United Kingdom (L.C.); and Hammersmith Medicines Research, London, United Kingdom (D.W.).

An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 g [C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 g dose followed by an oral 800 g dose of [C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (F), proportion of nemiralisib escaping gut wall metabolism (F), hepatic extraction (E), fraction of dose absorbed from inhaled dose (F), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while F was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (F, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (F and E being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (F), the proportion of drug escaping first-pass extraction through the gut wall and liver (F and F) and hepatic extraction (E). Entero-test bile sampling enabled characterization of biliary elimination pathways.
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http://dx.doi.org/10.1124/dmd.119.088344DOI Listing
December 2019

Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules.

Pharmacol Res Perspect 2015 Oct 10;3(5):e00173. Epub 2015 Aug 10.

Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Research and Development 709 Swedeland Road, King of Prussia, Pennsylvania, 19406.

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution.
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http://dx.doi.org/10.1002/prp2.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618644PMC
October 2015

Metabolism and disposition of vilanterol, a long-acting β(2)-adrenoceptor agonist for inhalation use in humans.

Drug Metab Dispos 2013 Jan 4;41(1):89-100. Epub 2012 Oct 4.

Division of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom.

The metabolism and disposition of vilanterol, a novel long-acting β(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 μg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration.
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http://dx.doi.org/10.1124/dmd.112.048603DOI Listing
January 2013

Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds.

Chem Res Toxicol 2012 Oct 19;25(10):2067-82. Epub 2012 Sep 19.

Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Park Road, Ware, Hertfordshire SG12 0DP, United Kingdom.

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.
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http://dx.doi.org/10.1021/tx300075jDOI Listing
October 2012

Localization of artesunate and its derivatives in the pregnant rat and fetus following oral administration and relationship to developmental toxicity.

Birth Defects Res B Dev Reprod Toxicol 2010 Oct;89(5):364-75

Artemis Pharmaceutical Research, Lansdale, Pennsylvania 19446, USA.

Background: The antimalarial drug artesunate affects erythroid cells leading to developmental toxicity and adult reticulocytopenia. We report on a kinetic study in rats and the tissue distribution of radioactivity following oral administration of [(3)H]-artesunate to pregnant rats using quantitative whole-body autoradiography (QWBA).

Methods: Rats were dosed orally with chlorproguanil/dapsone/artesunate (including 11.8 mg/kg artesunate) and plasma concentrations of artesunate and the active metabolite dihydroartemisinin (DHA) were determined. In the QWBA study, 6 rats received 13 mg/kg [(3)H]-artesunate on day 18 of gestation. Groups of 2 rats were euthanized at 1, 6, and 24 hours after dosing, rapidly frozen, and sectioned in a cryostat. Sagittal sections were freeze-dried and placed in contact with imaging plates. Tissue concentrations of radioactivity were quantified.

Results: Systemic exposure to DHA was up to 22-fold higher than the parent compound and was higher in non-pregnant females than males. In the QWBA study, high concentrations of radioactivity were seen in maternal tissues involved in absorption and excretion, the bone marrow and spleen. Fetal blood and liver levels were 3.8- to 8.8-fold higher than maternal blood levels at all timepoints.

Conclusions: Excluding tissues involved in absorption and excretion, the highest concentrations of radioactivity were observed in tissues involved in hemoglobin synthesis and/or destruction in both the mother and the fetus and likely account for the maternal reticulocytopenia and embryotoxicity. Radioactivity concentrations in the fetal blood were 2.1- to 2.8-fold higher than maternal bone marrow at all timepoints and this difference could contribute to the lower dose threshold for embryotoxicity.
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http://dx.doi.org/10.1002/bdrb.20256DOI Listing
October 2010

Formation and protein binding of the acyl glucuronide of a leukotriene B4 antagonist (SB-209247): relation to species differences in hepatotoxicity.

Drug Metab Dispos 2005 Feb 2;33(2):271-81. Epub 2004 Nov 2.

Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3GE, UK.

SB-209247 [(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid], an anti-inflammatory leukotriene B4 receptor antagonist, was associated in beagle dogs but not male rats with an inflammatory hepatopathy. It also produced a concentration-dependent (10-1000 microM) but equal leakage of enzymes from dog and rat precision-cut liver slices. The hepatic metabolism of SB-209247 was investigated with reference to the formation of reactive acyl glucuronides. [14C]SB-209247 (100 micromol/kg) administered i.v. to anesthetized male rats was eliminated by biliary excretion of the acyl glucuronides of the drug and its sulfoxide. After 5 h, 1.03 +/- 0.14% (mean +/- S.E.M., n = 4) of the dose was bound irreversibly to liver tissue. The sulfoxide glucuronide underwent pH-dependent rearrangement in bile more rapidly than did the SB-209247 conjugate. [14C]SB-209247 was metabolized by sulfoxidation and glucuronidation in rat and dog hepatocytes, and approximately 1 to 2% of [14C]SB-209247 (100 microM) became irreversibly bound to cellular material. [14C]SB-209247 sulfoxide and glucuronide were the only metabolites produced by dog, rat, and human liver microsomes in the presence of NADPH and UDP-glucuronic acid (UDPGA), respectively. V(max) values for [14C]SB-209247 glucuronidation by dog, rat, and human microsomes were 2.6 +/- 0.1, 1.2 +/- 0.1, and 0.4 +/- 0.0 nmol/min/mg protein, respectively. Hepatic microsomes from all three species catalyzed UDPGA-dependent but not NADPH-dependent irreversible binding of [14C]SB-209247 (100-250 microM) to microsomal protein. Although a reactive acyl glucuronide was formed by microsomes from every species, the binding did not differ between species. Therefore, neither the acute cellular injury nor glucuronidation-driven irreversible protein binding in vitro is predictive of the drug-induced hepatopathy.
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http://dx.doi.org/10.1124/dmd.104.001677DOI Listing
February 2005