Publications by authors named "Sophie Lachau-Durand"

16 Publications

  • Page 1 of 1

Exacerbation of Background Nuclear Cataracts in Sprague-Dawley Rats in Embryo-Fetal Development Studies With JNJ-42165279, a Fatty Acid Amide Hydrolase Inhibitor.

Toxicol Pathol 2021 Jun 15:1926233211010444. Epub 2021 Jun 15.

Janssen Research & Development, LLC, San Diego, CA, USA.

Fetal examinations in embryo-fetal developmental (EFD) studies are based on macroscopic and dissecting microscopic evaluations, and histopathology is rarely performed other than to confirm macroscopic findings. Fetal lens examination is therefore generally limited to the presence, size, shape, and color of any abnormality. In a Sprague-Dawley rat EFD study with the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279, an unusually high incidence of macroscopic granular foci was noted within the lens of gestation day 21 fetuses across all groups including controls, with higher incidence in the high-dose group. On histological evaluation of the lenses from fetuses with/without gross findings, primary lens fiber hypertrophy (swelling) and degeneration were observed across vehicle- and JNJ-42165279-exposed fetuses. In a follow-up study to investigate the progression or resolution of the fetal lens changes, animals exposed to suprapharmacological doses of JNJ-42165279 in utero had higher incidence of nuclear cataracts as detected via slit-lamp ophthalmic examinations on postnatal days 18 to 21 and 35 to 41. No histologic correlates for these cataracts were identified. We conclude that fetal primary lens fiber hypertrophy and nuclear cataracts at ophthalmology, are common background changes in this rat strain that are exacerbated by in utero exposure to the FAAH inhibitor JNJ-42165279.
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http://dx.doi.org/10.1177/01926233211010444DOI Listing
June 2021

Design, Formulation, and Evaluation of Novel Dissolving Microarray Patches Containing Rilpivirine for Intravaginal Delivery.

Adv Healthc Mater 2019 05 6;8(9):e1801510. Epub 2019 Mar 6.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.

Antiretroviral (ARV) drugs have, for many years, been studied and administered in the prevention and treatment of human immunodeficiency virus (HIV). Intramuscular (IM) injection of long acting (LA) ARVs are in clinical development, but injectable formulations require regular access to healthcare facilities and disposal facilities for sharps. The development of a discrete, self-administered, and self-disabling vehicle to deliver ARVs could obviate these issues. This study describes the formulation, mechanical characterization, and in vivo evaluation of dissolving microarray patches (MAPs) containing a LA nanosuspension of the ARV, rilpivirine (RPV, RPV LA), for vaginal delivery. This is the first study to apply MAPs into vaginal tissue. The RPV LA MAPs penetrate ex vivo skin and a synthetic vaginal skin model and withstand the effects of potential dragging motion across synthetic vaginal epithelium. In in vivo studies, the mean plasma concentration of RPV in rats at the 56 day endpoint (116.5 ng mL ) is comparable to that achieved in the IM control cohort (118.9 ng mL ). RPV is detected systemically, in lymph and vaginal tissue, indicating the potential to deliver RPV LA to primary sites of viral challenge and replication. This innovative research has future potential for patients and healthcare workers, particularly in low-resource settings.
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http://dx.doi.org/10.1002/adhm.201801510DOI Listing
May 2019

Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection.

Antimicrob Agents Chemother 2019 04 27;63(4). Epub 2019 Mar 27.

Janssen R&D, Beerse, Belgium.

The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with rBCG30, BALB/c mice were challenged by aerosol infection with H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (B); and test regimens of daily bedaquiline at 2.67 mg/kg (B), 5.33 mg/kg (B), or 8 mg/kg (B) to deliver the same total amount of bedaquiline as one, two, or three doses of B, respectively. All drugs were administered orally, except for B (intramuscular injection). The primary outcome was the decline in lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of B resulted in decreases of 2.9, 3.2, and 3.5 log CFU/lung, respectively, by week 12. Daily oral dosing with B, B, and B decreased lung CFU counts by 1.6, 2.8, and 4.1 log, respectively. One dose of B exhibited activity for at least 12 weeks. The sustained activity of B indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.
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http://dx.doi.org/10.1128/AAC.00007-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437534PMC
April 2019

Macrofilaricidal efficacy of single and repeated oral and subcutaneous doses of flubendazole in Litomosoides sigmodontis infected jirds.

PLoS Negl Trop Dis 2019 01 16;13(1):e0006320. Epub 2019 Jan 16.

Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.

Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect.
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http://dx.doi.org/10.1371/journal.pntd.0006320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334906PMC
January 2019

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi.

PLoS Negl Trop Dis 2019 01 16;13(1):e0006787. Epub 2019 Jan 16.

Dept. of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.

River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2-15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.
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http://dx.doi.org/10.1371/journal.pntd.0006787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334909PMC
January 2019

Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk/benefit to patients.

PLoS Negl Trop Dis 2019 01 16;13(1):e0007026. Epub 2019 Jan 16.

Nonclinical Safety, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.

Background: Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of the flubendazole ASD formulation have been assessed to ensure human safety before clinical trials could be initiated.

Methods & Findings: Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15% in dogs, 27% in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce Cmax related effects in CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in dogs. In rats, the No Observed Adverse Effect Level (NOAEL) was 5 mg (as base)/kg body weight/day (mg eq./kg/day) in males and 2.5 mg eq./kg/day in females. In dogs, the NOAEL was lower than 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test, but positive in the in vivo micronucleus test.

Conclusions: Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure.
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http://dx.doi.org/10.1371/journal.pntd.0007026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334931PMC
January 2019

Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension.

J Control Release 2018 12 2;292:119-129. Epub 2018 Nov 2.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address:

One means of combating the spread of human immunodeficiency virus (HIV) is through the delivery of long-acting, antiretroviral (ARV) drugs for prevention and treatment. The development of a discreet, self-administered and self-disabling delivery vehicle to deliver such ARV drugs could obviate compliance issues with daily oral regimens. Alternatives in development, such as long-acting intramuscular (IM) injections, require regular access to health care facilities and disposal facilities for sharps. Consequently, this proof of concept study was developed to evaluate the use of dissolving microarray patches (MAPs) containing a long-acting (LA) nanosuspension of the candidate ARV drug, rilpivirine (RPV). MAPs were mechanically strong and penetrated skin in vitro, delivering RPV intradermally. In in vivo studies, the mean plasma concentration of RPV in rats (431 ng/ml at the Day 7 time point) was approximately ten-fold greater than the trough concentration observed after a single-dose in previous clinical studies. These results are the first to indicate, by the determination of relative exposures between IM and MAP administration, that larger multi-array dissolving MAPs could potentially be used to effectively deliver human doses of RPV LA. Importantly, RPV was also detected in the lymph nodes, indicating the potential to deliver this ARV agent into one of the primary sites of HIV replication over extended durations. These MAPs could potentially improve patient acceptability and adherence to HIV prevention and treatment regimens and combat instances of needle-stick injury and the transmission of blood-borne diseases, which would have far-reaching benefits, particularly to those in the developing world.
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http://dx.doi.org/10.1016/j.jconrel.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290172PMC
December 2018

Discovery of 1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2'-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3'-5'-Cyclic Phosphate Ester Prodrug of 2'-Deoxy-2'-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition.

J Med Chem 2016 06 3;59(12):5790-8. Epub 2016 Jun 3.

Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.

JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype (GT) 1b replicon-containing cell line 9 is devoid of any anti-HCV activity, an observation attributable to inefficient prodrug metabolism which was found to be CYP3A4-dependent. In contrast, in vitro incubation of 9 in primary human hepatocytes as well as pharmacokinetic evaluation thereof in different preclinical species reveals the formation of substantial levels of 2'-deoxy-2'-spirooxetane uridine triphosphate (8), a potent inhibitor of the HCV NS5B polymerase. Overall, it was found that 9 displays a superior profile compared to its phosphoramidate prodrug analogues (e.g., 4) described previously. Of particular interest is the in vivo dose dependent reduction of HCV RNA observed in HCV infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days of oral administration of 9.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00382DOI Listing
June 2016

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

J Pharm Sci 2016 09 22;105(9):2782-2793. Epub 2016 Apr 22.

Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium. Electronic address:

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.
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http://dx.doi.org/10.1016/j.xphs.2016.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988473PMC
September 2016

Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase.

J Med Chem 2014 Mar 6;57(5):1836-44. Epub 2014 Jan 6.

Janssen Infectious Diseases - Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.

The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.
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http://dx.doi.org/10.1021/jm4015422DOI Listing
March 2014

Discovery of 4'-azido-2'-deoxy-2'-C-methyl cytidine and prodrugs thereof: a potent inhibitor of Hepatitis C virus replication.

Bioorg Med Chem Lett 2012 May 16;22(9):3265-8. Epub 2012 Mar 16.

Medivir AB, PO Box 1086, SE-141 22 Huddinge, Sweden.

4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 μM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.
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http://dx.doi.org/10.1016/j.bmcl.2012.03.021DOI Listing
May 2012

Antiviral activity and mode of action of TMC647078, a novel nucleoside inhibitor of the hepatitis C virus NS5B polymerase.

Antimicrob Agents Chemother 2011 Aug 16;55(8):3812-20. Epub 2011 May 16.

Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.

Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed in vitro and in vivo suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the in vitro inhibitory activity and mode of action of 2'-deoxy-2'-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain. In vitro combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes in vitro. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising in vitro virology and biology profile.
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http://dx.doi.org/10.1128/AAC.00214-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147651PMC
August 2011

2'-Deoxy-2'-spirocyclopropylcytidine revisited: a new and selective inhibitor of the hepatitis C virus NS5B polymerase.

J Med Chem 2010 Nov 29;53(22):8150-60. Epub 2010 Oct 29.

Tibotec BVBA, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium.

The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 μM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 μM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.
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http://dx.doi.org/10.1021/jm101050aDOI Listing
November 2010

Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects.

Drug Metab Dispos 2009 Apr 8;37(4):809-20. Epub 2009 Jan 8.

Tibotec BVBA, Generaal De Wittelaan L 11B-3, B-2800 Mechelen, Belgium.

Absorption, metabolism, and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of [(14)C]darunavir given alone (unboosted subjects) or with ritonavir [100 mg b.i.d. 2 days before and 7 days after darunavir administration (boosted subjects)]. Plasma exposure to darunavir was 11-fold higher in boosted subjects. Total recoveries of radioactivity in urine and feces were 93.9 and 93.5% of administered radioactivity in unboosted and boosted subjects, respectively. The most radioactivity was recovered in feces (81.7% in unboosted subjects and 79.5% in boosted subjects, compared with 12.2 and 13.9% recovered in urine, respectively). Darunavir was extensively metabolized in unboosted subjects, mainly by carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation and to a lesser extent by benzylic aromatic hydroxylation and glucuronidation. Total excretion of unchanged darunavir accounted for 8.0% of the dose in unboosted subjects. Boosting with ritonavir resulted in significant inhibition of carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation but had no effect on aromatic hydroxylation at the benzylic moiety, whereas excretion of glucuronide metabolites was markedly increased but still represented a minor pathway. Total excretion of unchanged darunavir accounted for 48.8% of the administered dose in boosted subjects as a result of the inhibition of darunavir metabolism by ritonavir. Unchanged darunavir in urine accounted for 1.2% of the administered dose in unboosted subjects and 7.7% in boosted subjects, indicating a low renal clearance. Darunavir administered alone or with ritonavir was well tolerated.
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http://dx.doi.org/10.1124/dmd.108.024109DOI Listing
April 2009

Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K.

Toxicol Pathol 2008 Feb 26;36(2):321-9. Epub 2008 Mar 26.

Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.

Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys.
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http://dx.doi.org/10.1177/0192623307311404DOI Listing
February 2008

Dog model with implanted pump to test boosters for antiretroviral medication.

Int J Pharm 2008 May 25;355(1-2):45-52. Epub 2007 Sep 25.

Chem-Pharm Development, Tibotec BVBA, Gen. De Wittelaan L11B 3, 2800 Mechelen, Belgium.

A dog model was developed to test the capacity of boosters for antiretroviral medication. Two dogs were implanted with a modified constant-flow Codman 3000 infusion pump, adapted to release viscous solutions of darunavir (TMC114) at a constant rate of 25mg/dog/day in the venous blood stream. Booster candidates were given by oral gavage for at least 4 days up to maximum 7 days in cross-over fashion, separated by a wash-out period of minimum 1 week. The booster candidates were tested at doses of 20 and/or 40mg/kg/day: blood sampling for determination of the boosting effect was performed on the last day of booster administration. The model allowed to (1) compare the boosting ratio of these booster candidates based on the exposure (determination of the area under the curve (AUC) of darunavir in presence versus absence of the booster candidate), (2) detect delay in boosting activity by evaluation of the shift of Cmax of darunavir following booster administration versus the Cmax of the booster candidate) and (3) calculate the intrinsic booster capacity, by correcting for the systemic exposure of booster candidate by normalizing the booster ratio for the booster's AUC. The latter parameter (intrinsic booster capacity) allows to determine the booster's metabolic contribution in inhibiting the metabolism of antiretroviral medication (most likely via inhibition of CYP3A4), minimizing the impact of potential effects of the booster at the level of the gastro-intestinal tract.
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http://dx.doi.org/10.1016/j.ijpharm.2007.09.025DOI Listing
May 2008
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