Richard M. W. Hoetelmans

Bedaquiline: a review of human pharmacokinetics and drug–drug interactions

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.

Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers

This study compared the bioavailability of two 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 (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short‐term tolerability of the FDCs was comparable to 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.

Impact of food and different meal types on the pharmacokinetics of rilpivirine.

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.

Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir in healthy volunteers: A randomized, two‐way crossover trial

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.

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.

The effect of single‐ and multiple‐dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

The effect of etravirine on cytochrome P450 (CYP) enzymes and P‐glycoprotein were evaluated in two randomized, crossover 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 AUClast 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 isozyme inducer and minimally inhibits CYP2C9, 2C19, and P‐glycoprotein activity.

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.

Pharmacokinetics of darunavir after administration of an oral suspension with low‐dose ritonavir and with or without food

This 2‐part, phase 1, open‐label, randomized, crossover study (NCT00752310) assessed ritonavir‐boosted darunavir bioavailability (oral suspension vs. tablets), and steady‐state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a ≥7‐day washout between treatments; 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 in part 2 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.

The effect of rilpivirine on the pharmacokinetics of methadone in HIV‐negative volunteers

Antiretrovirals may influence methadone exposure in HIV‐1‐infected patients receiving methadone for opiate addiction. Rilpivirine is a non‐nucleoside 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.

Pharmacokinetics and Short-Term Safety of Etravirine in Combination With Fluconazole or Voriconazole in HIV-Negative Volunteers

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 [AUC12 h] 1.86‐ and 1.36‐fold, respectively). Fluconazole pharmacokinetics were unchanged with etravirine coadministration (AUC12 h LSM ratio: 0.94), and voriconazole plasma concentrations were slightly raised (AUC12 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.