Mechanistic Model Describing the Time Course of Humoral Immunity Following Ad26.COV2.S Vaccination in Non-Human Primates.

Mechanistic modeling can be used to describe the time course of vaccine-induced humoral immunity and to identify key biologic drivers in antibody production. We used a six-compartment mechanistic model to describe a 20-week time course of humoral immune responses in 56 non-human primates (NHPs) elicited by vaccination with Ad26.COV2.S according to either a single-dose regimen (1 × 1011 or 5 × 1010 viral particles [vp]) or a two-dose homologous regimen (5 × 1010 vp) given in an interval of 4 or 8 weeks. Humoral immune responses were quantified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific binding antibody concentrations as determined by spike protein-enzyme-linked immunosorbent assay. The mechanistic model adequately described the central tendency and variability of binding antibody concentrations through 20 weeks in all vaccination arms. The estimation of mechanistic modeling parameters revealed greater contribution of the antibody production mediated by short-lived cells as compared with long-lived cells in driving the peak response, especially post second dose when a more rapid peak response was observed. The antibody production mediated by long-lived cells was identified as relevant for generating the first peak and for contributing to the long-term time course of sustained antibody concentrations in all vaccination arms. The findings contribute evidence on the key biologic components responsible for the observed time course of vaccine-induced humoral immunity in NHPs and constitute a step toward defining immune biomarkers of protection against SARS-CoV-2 that might translate across species. SIGNIFICANCE STATEMENT: We demonstrate the adequacy of a mechanistic modeling approach describing the time course of binding antibody concentrations in non-human primates (NHPs) elicited by different dose levels and regimens of Ad26.COV2.S. The findings are relevant for informing the mechanism-based accounts of vaccine-induced humoral immunity in NHPs and translational research efforts aimed at identifying immune biomarkers of protection against SARS-CoV-2 infection.

Single- and multiple-dose pharmacokinetics and safety of pimodivir, a novel, non-nucleoside polymerase basic protein 2 subunit inhibitor of the influenza A virus polymerase complex, and interaction with oseltamivir: a Phase 1 open-label study in healthy volunteers.

AIMS: The aim of this study was to evaluate the drug-drug interaction between pimodivir, a novel, non-nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single- and multiple-dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed. METHODS: In Part 1 of this open-label Phase 1 study, healthy volunteers (n = 18) were randomized to one of six cross-over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof twice daily on Days 1-4, followed by a single morning dose on Day 5. Between each treatment session, there was a minimum 5-day washout period. In Part 2, healthy volunteers (n = 16) randomly received pimodivir 600 mg or placebo (3:1) twice daily on Days 1-9, followed by a single morning dose on Day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate, and safety were assessed. RESULTS: In Part 1, co-administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90% CI: 0.92-1.85) with no change in Cmin or AUC12h . Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single- and multiple-dose administration of pimodivir, there was a 1.2- and 1.8-fold increase in Cmax and AUC12h , respectively, between Day 1 and Day 10. The most frequently reported treatment-emergent adverse event was diarrhoea (n = 7 each in Part 1 and 2). CONCLUSION: Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug-drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily.

Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir.

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.

Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers.

UNLABELLED: 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.

Bioavailability and bioequivalence of a darunavir 800-mg tablet formulation compared with the 400-mg tablet formulation.

UNLABELLED: 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 × 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 × 400-mg tablets (reference) or 1 × 800- mg tablet (test) on day 3 and vice versa after a ≥ 7-day wash-out. Each study had fasted (n = 16 (bioavailability); 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-∞)) 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-∞) (fed and fasted conditions). Median time to C(max) was comparable for both formulations. 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.

Single-dose pharmacokinetics of pediatric and adult formulations of etravirine and swallowability of the 200-mg tablet: results from three Phase 1 studies.

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.

Quantifying Antibody Persistence After a Single Dose of COVID-19 Vaccine Ad26.COV2.S in Humans Using a Mechanistic Modeling and Simulation Approach.

Understanding persistence of humoral immune responses elicited by vaccination against coronavirus disease 2019 (COVID-19) is critical for informing the duration of protection and appropriate booster timing. We developed a mechanistic model to characterize the time course of humoral immune responses in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative adults after primary vaccination with the Janssen COVID-19 vaccine, Ad26.COV2.S. The persistence of antibody responses was quantified through mechanistic modeling-based simulations. Two biomarkers of humoral immune responses were examined: SARS-CoV-2 neutralizing antibodies determined by wild-type virus neutralization assay (wtVNA) and spike protein-binding antibodies determined by indirect spike protein enzyme-linked immunosorbent assay (S-ELISA). The persistence of antibody responses was defined as the period of time during which wtVNA and S-ELISA titers remained above the lower limit of quantification. A total of 442 wtVNA and 1,185 S-ELISA titers from 82 and 220 participants, respectively, were analyzed following administration of a single dose of Ad26.COV2.S (5 × 1010 viral particles). The mechanistic model adequately described the time course of observed wtVNA and S-ELISA serum titers and its associated variability up to 8 months following vaccination. Mechanistic model-based simulations show that single-dose Ad26.COV2.S elicits durable but waning antibody responses up to 24 months following immunization. Of the estimated model parameters, the production rate of memory B cells was decreased in older adults relative to younger adults, and the antibody production rate mediated by long-lived plasma cells was increased in women relative to men. A steeper waning of antibody responses was predicted in men and in older adults.

Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials.

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.

Pharmacokinetic interaction between indinavir and darunavir with low-dose ritonavir in healthy volunteers.

OBJECTIVE: To investigate the potential for a pharmacokinetic interaction between darunavir (DRV, TMC114, Prezista), indinavir (IDV, Crixivan) and low-dose ritonavir (RTV, Norvir). METHODS: In three 7-day sessions, 17 HIV-negative healthy volunteers received treatment A (DRV/r 400/100 mg b.i.d.), treatment B (IDV/r 800/100 mg b.i.d.) and treatment C (DRV/r 400/100 mg b.i.d. + IDV 800 mg b.i.d.). On day 7, full pharmacokinetic profiles of DRV, IDV and RTV were determined. Safety and tolerability were also assessed. RESULTS: Based on the least-squares means ratios, the steady-state exposure (area under the curve, AUC(12h)) and plasma concentrations (C(min) and C(max)) of IDV were increased by 23, 125 and 8%, respectively, when DRV was co-administered. The co-administration of IDV with DRV/r resulted in increases of 24, 44 and 11% for, respectively, DRV AUC(12h), C(min) and C(max), compared with administration of DRV/r alone. Eight volunteers discontinued due to an adverse event. Overall, adverse events and laboratory abnormalities were more commonly reported during treatments including IDV. CONCLUSIONS: When used in combination with DRV/r, dose adjustment of IDV from 800 mg b.i.d. to 600 mg b.i.d. may be warranted in cases of intolerance.

Pharmacokinetic interaction between nevirapine and darunavir with low-dose ritonavir in HIV-1-infected patients.

AIM: To investigate the pharmacokinetic interaction between darunavir/ritonavir (DRV/r) and nevirapine (NVP) in 19 HIV-infected patients. METHODS: An open-label, randomized, crossover study. Patients received Treatment A [NVP 200 mg b.i.d. plus > or =2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] and Treatment B [A plus DRV/r 300/100 mg b.i.d. (DRV oral solution)] or Treatment B2 [A plus DRV/r 400/100 mg b.i.d. (DRV tablet)] in two 14-day sessions. RESULTS: Mean NVP AUC(12h) increased by 27% [least square means ratio 1.27 (95% confidence interval 1.02, 1.58)]. Mean DRV and ritonavir exposures were similar to historical data. Co-administration was well tolerated. CONCLUSIONS: DRV/r and NVP have no clinically relevant interaction. No dose adjustments are required.

Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects.

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC(0-12)), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (C(max)), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C(12)); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC(0-12), 1.04 (0.97, 1.12) for C(max), and 1.17 (1.10, 1.26) for C(12). All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

Darunavir: pharmacokinetics and drug interactions.

Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains. Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose. The t1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir. An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas. Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable. For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required. This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals.

Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women.

BACKGROUND: An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women. METHODS: In session 1, participants received 35 microg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session. RESULTS: Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters. CONCLUSIONS: The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r.

Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients.

BACKGROUND: An open-label, randomized, crossover study to evaluate the pharmacokinetics of two different formulations of etravirine after single and multiple dosing. METHODS: Treatment-experienced HIV-1-infected patients with viral load <50 copies/ml continued their current antiretroviral regimen and added etravirine twice daily for 7 days with a morning intake on day 8. Etravirine was administered following food as either 800 mg twice daily of the Phase II formulation or 100 mg or 200 mg twice daily of the Phase III formulation. A 12 h pharmacokinetic assessment was performed on days 1 and 8. RESULTS: After single- and multiple-dose administration, the exposure to etravirine was lower with 100 mg twice daily and higher with 200 mg twice daily compared with 800 mg twice daily. On day 8, the mean (+/-SD) area under the plasma concentration-time curve over 12 h (AUC0-12 h) was 1,284 (+/-958) ng x h/ml when etravirine was administered as 100 mg twice daily (n=33), 3,713 (+/-2,069) ng x h/ml when administered as 200 mg twice daily (n=27) and 2,607 (+/-2,135) ng x h/ml when administered as 800 mg twice daily (n=32). Both formulations and all doses of etravirine tested were generally safe and well tolerated. CONCLUSIONS: The range of exposure to etravirine was comparable between 200 mg twice daily dose and 800 mg twice daily. The Phase III formulation of etravirine significantly improves the bioavailability of etravirine over the Phase II formulation with reduced interpatient variability in etravirine pharmacokinetics.

Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers.

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC(24h), C(max), and C(min) of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC125.

Darunavir/ritonavir pharmacokinetics following coadministration with clarithromycin in healthy volunteers.

This study investigated the steady-state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low-dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV-negative healthy volunteers. In a 3-way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14-hydroxy-clarithromycin plasma concentrations were reduced to below the lower limit of quantification (<50 ng/mL). The study medication was generally well tolerated. Based on these pharmacokinetic findings, neither clarithromycin nor darunavir/ritonavir dose adjustments are necessary when clarithromycin is coadministered with darunavir/ritonavir.

A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers.

AIMS: Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. METHODS: In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. RESULTS: Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. CONCLUSIONS: Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.

Effects of different meal compositions and fasted state on the oral bioavailability of etravirine.

STUDY OBJECTIVE: To determine the effects of various meal compositions and the fasted state on the pharmacokinetics of etravirine, a nonnucleoside reverse transcriptase inhibitor. DESIGN: Phase I, open-label, randomized, repeated single-dose, three-period crossover trial. SETTING: Clinical pharmacology unit. PARTICIPANTS: Two parallel panels of 12 human immunodeficiency virus (HIV)-negative, healthy, male volunteers. Twenty volunteers completed the study; three withdrew consent, and one was lost to follow-up. Intervention. Panel 1 received a single dose of etravirine 100 mg after a standard breakfast, in the fasted state, and after a light breakfast (croissant). Panel 2 received the same treatment after a standard breakfast, after an enhanced-fiber breakfast, and after a high-fat breakfast. Each treatment was separated by a washout period of at least 14 days. MEASUREMENTS AND MAIN RESULTS: For each treatment, full pharmacokinetic profiles of etravirine were determined up to 96 hours after dosing. Pharmacokinetic parameters were determined by noncompartmental methods and analyzed using a linear mixed-effects model for a crossover design. The least-squares mean ratio for the area under the plasma concentration-time curve from time of administration to the last time point with a measurable concentration after dosing (AUClast) was 0.49 (90% confidence interval [CI] 0.39-0.61) for the fasted state compared with dosing after a standard breakfast. When dosing occurred after a light or enhanced-fiber breakfast, the corresponding values were 0.80 (90% CI 0.69-0.94) and 0.75 (90% CI 0.63-0.90), respectively. When administered after a high-fat breakfast the least-squares mean ratio of AUC(last) was 1.09 (0.84-1.41), compared with dosing after a standard breakfast. Adverse events were also assessed. Under all conditions, single doses of etravirine 100 mg were generally safe and well tolerated. CONCLUSION: Administration of etravirine in a fasted state resulted in 51% lower mean exposure compared with dosing after a standard breakfast. Etravirine should be administered following a meal to improve bioavailability; however, differences in exposure after a standard breakfast versus a high-fat, enhanced-fiber, or light breakfast (croissant) were not considered clinically relevant.