Richard M W Hoetelmans

Janssen Research & Development, LLC, Raritan, New Jersey, United States

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Publications (166)541.17 Total impact

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    ABSTRACT: Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden. Objectives: To assess the relative oral bioavailability (NCT01052883) and bioequivalence (NCT01308658) of a darunavir 800-mg tablet vs. 2 x 400-mg tablets. Methods: In two phase I, open-label, randomized, crossover, single-center studies, healthy volunteers received once-daily ritonavir (100 mg, days 1 - 5) and a single 800-mg darunavir dose: 2 x 400-mg tablets (reference) or 1 x 800-mg tablet (test) on day 3 and vice versa after a >= 7-day wash-out. Each study had fasted (n = 16 (bioav. ailability); n = 83 (bioequivalence)) and fed panels (n = 16; n = 45, respectively). Pharmacokinetic profiles and tolerability were assessed. Results: No volunteers discontinued for treatment-related reasons. Least-square mean ratios (test vs. reference) for darunavir maximum plasma concentrations (C-max), area under the concentration-time curve from zero to infinity (AUC(0-infinity)) were: 1.06 and 1.15 (bioavailability), and 1.02 and 1.00 (bioequivalence), respectively (fasted); 0.89 and 0.88 (bioavailability), and 0.96 and 0.98 (bioequivalence), respectively (fed). 90% confidence intervals (CI) were within 80.00 - 125.00%, except bioavailability AUC(0-infinity) (fed and fasted conditions). Median time to C-max was comparable for both fonnulations. No clinically relevant differences in adverse events or laboratory abnormalities occurred between formulations. Conclusions: Bioequivalence was demonstrated for the 800-mg darunavir tablet (fasted and fed conditions). This formulation can reduce pill burden and potentially increase adherence for HIV-1-infected patients in whom once-daily darunavir/ritonavir 800/100 mg is appropriate.
    International journal of clinical pharmacology and therapeutics 09/2014; 52(9):805-16. DOI:10.5414/CP202066 · 1.04 Impact Factor
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    ABSTRACT: This 2-part, phase 1, open-label, randomized, crossover study (NCT00752310) assessed ritonavir-boosted darunavir bioavailability (oral suspension versus tablets), and steady-state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a ≥7-day washout; twice-daily ritonavir (100 mg, days 1–5) with darunavir (600 mg, day 3) as 2 × 300-mg tablets (fed, reference), or 6 mL of a 100-mg/mL suspension (fed or fasted, test). Part 2: 18 healthy volunteers received twice-daily darunavir (suspension, 600 mg days 1–6, one dose day 7) with twice-daily ritonavir (100 mg, days 1–9). Darunavir pharmacokinetics were evaluated (part 1 day 3; part 2 day 7). Safety/tolerability were assessed. In part 1, 90% confidence intervals for darunavir Cmax and AUC were all within 80%–125% for suspension (fed or fasted) versus tablets (fed). Steady-state darunavir (suspension) pharmacokinetics were similar to historic controls (tablets). No clinically relevant differences in adverse events or laboratory abnormalities occurred between treatments. Darunavir administered as an oral suspension or tablets (both with low-dose ritonavir) showed comparable bioavailability in healthy adults after a single dose. Steady-state darunavir pharmacokinetics (suspension, 600/100 mg twice daily) were consistent with historic controls; this formulation is considered suitable for pediatric use and for adults who cannot swallow tablets.
    09/2014; 3(5). DOI:10.1002/cpdd.88
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    ABSTRACT: This study compared the bioavailability of 2 candidate fixed-dose combinations (FDCs: G003 and G004) of darunavir/cobicistat 800/150 mg with that of darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short-term safety and tolerability of the FDC formulations were also assessed. This open-label trial included 36 healthy volunteers and assessed steady-state pharmacokinetics of darunavir over 3 randomized, 10-day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid-chromatography tandem mass-spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng•h/mL and G004: 76,490 ng•h/mL) was comparable to that following darunavir/ritonavir (78,410 ng•h/mL), as was Cmax (6666 and 6917 ng/mL versus 6973 ng/mL, respectively). Modestly lower C0h (1504 and 1478 ng/mL versus 2015 ng/mL) and Cmin (1167 and 1224 ng/mL versus 1540 ng/mL) values were seen with the FDCs. Short-term tolerability of the FDCs was comparable with that of darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset or rash. Cobicistat is an effective pharmacoenhancer of darunavir when administered as an FDC. Short-term administration of darunavir/ritonavir or darunavir/cobicistat was generally well tolerated.
    The Journal of Clinical Pharmacology 08/2014; 54(8). DOI:10.1002/jcph.290 · 2.47 Impact Factor
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    ABSTRACT: The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment-experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily.
    Journal of Antimicrobial Chemotherapy 06/2014; 69(10). DOI:10.1093/jac/dku193 · 5.44 Impact Factor
  • R P G van Heeswijk, B Dannemann, R M W Hoetelmans
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    ABSTRACT: Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.
    Journal of Antimicrobial Chemotherapy 05/2014; 69(9). DOI:10.1093/jac/dku171 · 5.44 Impact Factor
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    ABSTRACT: Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, rilpivirine or etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals. Telaprevir minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the concentration-time curve (AUC) decreased 25%, 10%, and 16%, respectively, when coadministered with etravirine and 11%, 3%, and 5%, respectively, when coadministered with rilpivirine. Telaprevir did not affect etravirine pharmacokinetics, but increased rilpivirine Cmin, Cmax, and AUC by 93%, 49%, and 78%, respectively. Both combinations were generally well tolerated. The small decrease in telaprevir exposure when coadministered with etravirine is unlikely to be clinically relevant. The interaction between telaprevir and rilpivirine is not likely to be clinically relevant under most circumstances. No dose adjustments are deemed necessary when they are coadministered. © 2013, The American College of Clinical Pharmacology.
    The Journal of Clinical Pharmacology 05/2014; 54(5). DOI:10.1002/jcph.245 · 2.47 Impact Factor
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    ABSTRACT: The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, cross over trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan) and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.
    The Journal of Clinical Pharmacology 04/2014; 54(4). DOI:10.1002/jcph.214 · 2.47 Impact Factor
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    ABSTRACT: Antiretrovirals may influence methadone exposure in HIV-1-infected patients receiving methadone for opiate addiction. Rilpivirine is a nonnucleoside reverse transcriptase inhibitor for treating HIV-1 infection. In this open-label trial (NCT00744770), 13 HIV-negative volunteers continued on their regular stable methadone therapy (60 to 100 mg once daily; days -14 to 12), with rilpivirine coadministration (days 1 to 11). Methadone and rilpivirine pharmacokinetics and opiate withdrawal symptoms (Short Opiate Withdrawal Scale, Desires for Drugs Questionnaire, pupillometry) were evaluated. Rilpivirine decreased methadone minimum and maximum plasma concentrations (Cmin ; Cmax ) and area under the plasma concentration-time curve versus methadone alone (least-square mean ratio; 90% confidence interval) by 22% (0.78; 0.67, 0.91), 14% (0.86; 0.78, 0.95), and 16% (0.84; 0.74, 0.95), respectively (R-methadone), and 21% (0.79; 0.67, 0.92), 13% (0.87; 0.78, 0.97), and 16% (0.84; 0.74, 0.96), respectively (S-methadone). Rilpivirine pharmacokinetics with methadone were consistent with historic data. No clinically relevant opiate withdrawal symptoms were reported. Methadone and rilpivirine coadministration was generally well tolerated. No grade 3/4 adverse events (AEs), serious AEs, or discontinuations due to AEs were seen. No methadone dose adjustment is prompted by rilpivirine coadministration. Clinical monitoring for opiate withdrawal is recommended, as some patients may require adjustment of methadone maintenance therapy.
    The Journal of Clinical Pharmacology 02/2014; 54(2). DOI:10.1002/jcph.222 · 2.47 Impact Factor
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    ABSTRACT: Rilpivirine is a human immunodeficiency virus Type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. Objective: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials. gov number: NCT00739622) evaluated the interaction between rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives), which are metabolized by multiple pathways, including CYP3A4. Methods: During three consecutive 28-day cycles, 18 HIV-negative females received once-daily ethinylestradiol (35 μg)/norethindrone (1 mg) (Days 1 - 21); Days 22 - 28 were pill-free. Only in Cycle 3 was once-daily rilpivirine (25 mg) co-administered (Days 1 - 15). Minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15, Cycles 2 and 3) and rilpivirine (Day 15, Cycle 3) were evaluated. Results: Rilpivirine coadministration had no effect on (least square mean ratio, 90% confidence interval) ethinylestradiol Cmin (1.09, 1.03 - 1.16) or AUC24h (1.14, 1.10 - 1.19), but increased Cmax by 17% (1.17, 1.06 - 1.30), which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC24h: 0.89, 0.84 - 0.94; Cmin: 0.99, 0.90 - 1.08; Cmax: 0.94, 0.83 - 1.06). Steady-state rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified. Conclusions: Co-administration of rilpivirine, at the therapeutic dosing regimen, with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics, and is, therefore, unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification.
    International journal of clinical pharmacology and therapeutics 10/2013; 52(02). DOI:10.5414/CP201943 · 1.04 Impact Factor
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    ABSTRACT: Drug-drug interactions between etravirine and rifabutin or clarithromycin were examined in two separate open-label, randomized, two-period, crossover trials in HIV-negative, healthy volunteers. Rifabutin study: 16 participants received 300 mg of rifabutin once daily (14 days) and then 800 mg of etravirine twice daily (Phase 2 formulation; 21 days) plus 300 mg of rifabutin once daily (days 8-21). Clarithromycin study: 16 participants received 200 mg of etravirine twice daily (commercial formulation; 8 days) and then 500 mg of clarithromycin twice daily (13 days) plus 200 mg of etravirine twice daily (days 6-13). A 14 day washout period between treatments was mandatory in both studies. Full pharmacokinetic profiles of each drug and safety/tolerability were assessed. Rifabutin decreased etravirine exposure by 37%; etravirine decreased rifabutin and 25-O-desacetyl rifabutin exposure by 17%. Clarithromycin increased etravirine exposure by 42%, whereas etravirine decreased clarithromycin exposure by 39% and increased 14-OH clarithromycin exposure by 21%. No serious adverse events were reported in either trial. Short-term etravirine coadministration with rifabutin or clarithromycin was well tolerated. Etravirine can be coadministered with 300 mg of rifabutin once daily in the absence of an additional potent cytochrome P450 inducer. No dose adjustments are required upon etravirine/clarithromycin coadministration, but alternatives to clarithromycin are recommended when used for Mycobacterium avium complex prophylaxis or treatment.
    Journal of Antimicrobial Chemotherapy 10/2013; 69(3). DOI:10.1093/jac/dkt421 · 5.44 Impact Factor
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    ABSTRACT: To evaluate safety, tolerability and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. Healthy participants aged 18 to 55 years with body mass index 18 to 30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 (administered alone or with 100 mg ritonavir twice daily [bid]) in the subsequent open-label phase. The multiple-dose, double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 (300 mg bid, 600 mg once daily [qd] or 150 mg bid [plus 100 mg ritonavir bid], 900 mg bid [alone] or 300 mg bid [plus ritonavir 50 mg bid]); in all sessions TMC310911 and ritonavir were administered for 6 and 9 days, respectively. In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner following the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and AUC values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. TMC310911 exhibited a linear pharmacokinetic profile following single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2013; 65(3). DOI:10.1097/QAI.0000000000000011 · 4.39 Impact Factor
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    ABSTRACT: TMC310911 is a novel human immunodeficiency virus type-1 (HIV-1) protease inhibitor with broad in vitro antiviral activity. In this phase 2a, open-label, randomized study, the antiviral activity, pharmacokinetics, and safety and tolerability of ritonavir-boosted TMC310911 was assessed. In this study, treatment-naïve HIV-1 patients (aged 18 to 60 years) received one of the 4 dosing regimens of TMC310911: 150 mg twice-daily (bid) (n=8), 300 mg bid (n=8), 75 mg bid (n=9), or 300 mg once-daily (qd) (n=8), for 14 days, all coadministered with 100 mg ritonavir, as only antiretroviral therapy. The mean change from baseline in HIV-1 RNA (log10 copies/mL; primary efficacy endpoint) was -1.30 (75 mg bid), -1.14 (150 mg bid), -1.07 (300 mg bid), and -1.06 (300 mg qd), on day 8 and -1.53 (75 mg bid), -1.79 (150 mg bid), -1.69 (300 mg bid), and -1.55 (300 mg qd) on day 15. At steady-state (day 14), the mean maximum plasma concentration and mean area under the plasma concentration-time curve from 0 to 12 hours tended to increase dose proportionally for bid doses; TMC310911 daily exposures for the 300 mg qd treatment and 150 mg bid treatment were comparable. The most common (≥10%) treatment-emergent adverse events (TEAEs) were fatigue (27.3 %) and nausea (12.1%); no deaths or serious TEAEs were reported in this study. Combination treatment with TMC310911 and ritonavir showed potent antiviral activity (>1.5 log10 copies/mL decrease in plasma HIV-1 RNA) at all evaluated doses and treatment was generally safe and well tolerated.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2013; 65(3). DOI:10.1097/QAI.0000000000000003 · 4.39 Impact Factor
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    ABSTRACT: Objectives: Three studies were conducted to assess the pharmacokinetics, methods of administration and ease of swallowability of etravirine tablets. Methods: Two randomized studies in healthy adults investigated the single-dose pharmacokinetics of etravirine in various dosage strengths and the effects of dispersion in water and film-coating. A third study explored swallowability of etravirine 200-mg tablets in HIV-infected patients. First study: 37 volunteers received 1 × 100-mg non-coated tablet (reference), 4 × 25-mg noncoated tablets and 1 × 100-mg non-coated tablet dispersed in 100 ml water. Second study: 24 volunteers received 2 × 100-mg non-coated tablets (reference), 2 × 100-mg coated tablets, 1 × 200-mg non-coated and 1 × 200-mg coated tablet. Pharmacokinetic parameters were determined using non-compartmental analysis and least square means (LSM) ratios and 90% confidence intervals (CI) were calculated. Third study: 49 virologically-suppressed patients already on an etravirine-containing regimen rated the swallowability of two etravirine formulations (200-mg non-coated and 200-mg coated tablets). Results: In the first study LSM ratios (90% CI) for the etravirine area under the plasma concentration-time curve (AUC) administered either as 4 × 25-mg tablets or 100-mg tablet dispersed were: 0.91 (0.85 to 0.98) and 0.97 (0.90 to 1.03), respectively. In the second study, when comparing a 200-mg non-coated and coated tablet to 2 × 100-mg non-coated tablets, LSM ratios for etravirine AUC were 98 to 99%. In the third study, more patients rated the 200-mg than the 100-mg tablets as acceptable to swallow (70% vs. 43%). Conclusions: Comparable etravirine exposures were observed regardless of formulation or method of administration (i.e., dispersion); 200-mg tablets were rated as easier to swallow than 100-mg tablets.
    International journal of clinical pharmacology and therapeutics 08/2013; 51(9). DOI:10.5414/CP201770 · 1.04 Impact Factor
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    ABSTRACT: The objective of the study was to determine the impact of food and different meal types on the pharmacokinetics of rilpivirine, a nonnucleoside reverse transcriptase inhibitor. In this open-label, randomized, crossover study, healthy volunteers received a single, oral 75 mg dose of rilpivirine either with a normal-fat breakfast (reference), under fasting conditions, with a high-fat breakfast, or with a protein-rich nutritional drink. Pharmacokinetic parameters were determined by non-compartmental methods and analyzed using a linear mixed-effects model. Safety was assessed throughout. The least-squares mean ratio for area under the plasma concentration-time curve to last timepoint was 0.57 (90% confidence interval [CI]: 0.46-0.72) under fasting conditions compared to dosing with a normal-fat breakfast. With a high-fat breakfast or only a protein-rich nutritional drink, the corresponding values were 0.92 (90% CI: 0.80-1.07) and 0.50 (90% CI: 0.41-0.61), respectively, compared to dosing with a normal-fat breakfast. Under all conditions, rilpivirine was generally safe and well tolerated. Administration of rilpivirine under fasting conditions or with only a protein-rich nutritional drink substantially lowered the oral bioavailability when compared to administration with a normal-fat breakfast. Rilpivirine bioavailability was similar when administered with a high-fat or normal-fat breakfast. Rilpivirine should always be taken with a meal to ensure adequate bioavailability.
    The Journal of Clinical Pharmacology 08/2013; 53(8). DOI:10.1002/jcph.107 · 2.47 Impact Factor
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    ABSTRACT: Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor approved in combination with other antiretrovirals for the treatment of HIV‑1 infection in treatment‑naive adults (Edurant® 25 mg once daily; Complera® [USA]/Eviplera® [EU] once daily single‑tablet regimen). Rilpivirine should be administered with a meal to optimize bioavailability. Its solubility is pH dependent. Rilpivirine is primarily excreted via the feces with negligible renal elimination. Rilpivirine is predominantly metabolized by cytochrome P450 3A4. There is no clinically relevant effect of age, gender, bodyweight, race, estimated glomerular filtration rate, or hepatitis B/C coinfection status on rilpivirine pharmacokinetics in adults. Drug‑drug interactions were investigated with cytochrome P450 3A substrates, inducers and inhibitors, drugs altering intragastric pH, antiretrovirals, and other often coadministered drugs. Rilpivirine 25 mg once daily does not have a clinically relevant effect on exposure of coadministered drugs. Coadministration with cytochrome P450 3A inhibitors (ketoconazole, ritonavir‑boosted protease inhibitors, telaprevir) results in increased rilpivirine plasma concentrations, but these are not considered clinically relevant; no dose adjustments are required. Coadministration of rilpivirine with cytochrome P450 3A inducers (e.g. rifampin, rifabutin) or compounds increasing gastric pH (e.g. omeprazole, famotidine) results in decreased rilpivirine plasma concentrations, which may increase the risk of virologic failure and resistance development. Therefore, strong cytochrome P450 3A inducers and proton‑pump inhibitors are contraindicated. Histamine‑2 receptor antagonists and antacids can be coadministered with rilpivirine, provided doses are temporally separated. No dose adjustments are required when rilpivirine is coadministered with: acetaminophen, phosphodiesterase type 5 inhibitors (sildenafil, etc.), atorvastatin (and other statins), oral contraceptives (ethinyl estradiol, norethindrone), chlorzoxazone (cytochrome P450 2E1 substrate), methadone, digoxin, tenofovir disoproxil fumarate, didanosine and other nuceos(t)ide reverse transcriptase inhibitors, and HIV integrase inhibitors (raltegravir, dolutegravir, GSK1265744).
    AIDS reviews 05/2013; 15(2):87-101. · 4.02 Impact Factor
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    ABSTRACT: A previous study investigating coadministration of etravirine, a nonnucleoside reverse transcriptase inhibitor, and lopinavir/ritonavir soft-gel formulation resulted in nonclinically relevant changes in etravirine and lopinavir exposure. The current study evaluated the pharmacokinetic interaction between etravirine and the lopinavir/ritonavir melt extrusion formulation. Sixteen human immunodeficiency virus (HIV)-negative volunteers were randomized to either treatment sequence A/B or B/A, with 14 days- washout between treatments (treatment A: etravirine 200 mg bid for 8 days; treatment B: lopinavir/ritonavir 400/100 mg bid for 16 days with etravirine 200 mg bid on days 9-16). Steady-state pharmacokinetics were assessed for all antiretrovirals alone and coadministered; pharmacokinetic parameters were obtained by noncompartmental analysis. Safety and tolerability were assessed. Coadministration of etravirine and lopinavir/ritonavir resulted in a 35% decrease in etravirine exposure. Smaller decreases (<13%) were observed in lopinavir and ritonavir exposure. Six volunteers reported headache; 1 grade 3 triglyceride increase was reported. Lopinavir/ritonavir induced etravirine metabolism to a similar extent as most other boosted HIV protease inhibitors. The short-term coadministration of etravirine and lopinavir/ritonavir was well tolerated and did not lead to increased incidences of adverse events.
    The Journal of Clinical Pharmacology 02/2013; 53(2):202-10. DOI:10.1177/0091270012445205 · 2.47 Impact Factor
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    ABSTRACT: The nonnucleoside reverse transcriptase inhibitor etravirine, approved for use in treatment-experienced, HIV-1-infected patients, is a substrate and inducer of cytochrome P450 (CYP) 3A4 and a substrate and inhibitor of CYP2C9/CYP2C19. Pharmacokinetic interactions and safety of etravirine 200 mg twice daily coadministered with fluconazole 200 mg daily or voriconazole 200 mg twice daily, both inhibitors of CYP3A4, CYP2C9, and CYP2C19, were evaluated in an open-label, randomized, 3-period crossover trial in 18 HIV-negative volunteers. Based on least squares means (LSM) ratios, coadministration of etravirine with fluconazole or voriconazole resulted in higher etravirine exposures (area under plasma concentration-time curve from 0-12 hours [AUC(12) (h) ] 1.86- and 1.36-fold, respectively). Fluconazole pharmacokinetics were unchanged with etravirine coadministration (AUC(12) (h) LSM ratio: 0.94), and voriconazole plasma concentrations were slightly raised (AUC(12) (h) LSM ratio: 1.14). All treatments and combinations were well tolerated, with no grade 3 or 4 adverse events observed during treatment. There was 1 adverse event-related trial withdrawal during treatment with fluconazole alone (leukocyturia). The most frequent adverse events were headache and blurred vision (11 and 8 volunteers, respectively), with blurred vision occurring exclusively during voriconazole-alone treatment. Pharmacokinetic interactions between etravirine and fluconazole or voriconazole are not expected to be clinically relevant; no dose adjustments are required during coadministration.
    The Journal of Clinical Pharmacology 01/2013; 53(1):41-50. DOI:10.1177/0091270011433329 · 2.47 Impact Factor
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    ABSTRACT: Rilpivirine (RPV, TMC278, Edurant®) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), which demonstrated high virologic response rates and non-inferiority versus efavirenz in two Phase III trials in HIV-infected patients through 96 weeks [1,2]. RPV has been shown to inhibit P-glycoprotein (P-gp) in vitro with an apparent IC50 of 9.2 µM (3.4 µg/mL). This study evaluated the in-vivo effect of steady-state RPV 25 mg once daily (qd) on the single-dose pharmacokinetics of the probe P-gp substrate digoxin. This was a Phase I, open-label, randomised, crossover trial in 22 HIV-negative volunteers. Participants received in one session a single 0.5 mg dose of digoxin, and in another session RPV 25 mg qd for 16 days with a single 0.5 mg dose of digoxin in the morning of Day 11. All study drugs were taken with a breakfast. Pharmacokinetic profiles of digoxin in plasma and urine were determined over 144 hours after dosing in each session. Steady-state RPV 24-hour pharmacokinetic profiles in plasma were determined on Day 11. Plasma and urine samples were analysed using validated LC-MS/MS methods. Pharmacokinetic parameters were calculated with non-compartmental methods. The least square (LS) means and associated 90% confidence intervals (CI) of treatment ratios were calculated based on log-transformed pharmacokinetic parameters. Safety and tolerability were assessed throughout the trial. Digoxin pharmacokinetic parameters and statistical results are summarised in Table 1. The plasma and urine digoxin pharmacokinetics were unaffected by co-administration of steady-state RPV. The 90% CIs of the LS means ratios of the main pharmacokinetic parameters were contained within the 0.80-1.25 boundaries of no effect. The terminal elimination half-life of digoxin was similar in the absence or the presence of steady-state RPV. RPV pharmacokinetic parameters were comparable to those in previous clinical trials in healthy volunteers. Administration of digoxin and RPV was generally safe and well tolerated. There were no discontinuations due to adverse events. In conclusion, RPV does not affect the pharmacokinetics of the probe P-gp substrate digoxin. In vivo, at the recommended RPV dose of 25mg qd, the observed in-vitro inhibition of P-gp by RPV is not clinically relevant.
    Journal of the International AIDS Society 11/2012; 15(6):18337. DOI:10.7448/IAS.15.6.18337 · 4.21 Impact Factor
  • Antimicrobial Agents and Chemotherapy 05/2011; · 4.45 Impact Factor
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    ABSTRACT: The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.
    Antimicrobial Agents and Chemotherapy 03/2011; 55(5):2290-6. DOI:10.1128/AAC.01046-10 · 4.45 Impact Factor

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  • 2014
    • Janssen Research & Development, LLC
      Raritan, New Jersey, United States
  • 2007–2011
    • Johnson & Johnson
      New Brunswick, New Jersey, United States
  • 2007–2008
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 2004
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2002–2003
    • The Thai Red Cross AIDS and Research Center
      Krung Thep, Bangkok, Thailand
    • University of New South Wales
      Kensington, New South Wales, Australia
    • The HIV Netherlands Australia Thailand Research Collaboration
      Krung Thep, Bangkok, Thailand
  • 2000–2002
    • University of Amsterdam
      • Department of Internal Medicine
      Amsterdam, North Holland, Netherlands
    • Boehringer Ingelheim
      Ingelheim-Mitte, Rheinland-Pfalz, Germany
  • 1995–2002
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2001
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Academic Medical Center
      Amsterdam, North Holland, Netherlands
  • 2000–2001
    • Utrecht University
      • Division of Biomedical Analysis
      Utrecht, Utrecht, Netherlands
  • 1998
    • Onze Lieve Vrouwe Gasthuis
      Amsterdamo, North Holland, Netherlands