Addressing bedaquiline treatment interruptions in the treatment of drug-resistant TB.

SETTING: The recommended dosing regimen for bedaquiline (BDQ), consisting of a 2-week loading phase (400 mg/day), followed by a maintenance phase (200 mg three times/week), might pose challenges when treatment is interrupted and needs to be reinitiated. Guidance on BDQ treatment re-initiation is, therefore, needed.OBJECTIVE: This pharmacokinetic-based simulation study aimed to provide recommendations for re-initiating BDQ following treatment interruptions.DESIGN: Simulations of treatment interruptions, defined as any time a patient misses ≥2 consecutive BDQ doses for up to 56 consecutive days (2 months), were assessed using the BDQ population-pharmacokinetic model.RESULTS: Any treatment interruption lasting ≤28 days prior to completing the 14-day loading phase can be managed by completing the remaining loading doses. Scenarios when it is sufficient to simply restart maintenance dosing are discussed. In some scenarios, treatment interruptions require reloading for 1 week prior to restarting maintenance dosing.CONCLUSIONS: This simulation study provided recommendations for managing BDQ treatment interruptions and underscores the importance of having a robust population-pharmacokinetic model for TB drugs to inform clinical guidance. Such recommendations are valuable to help ensure optimal treatment with BDQ for treating multidrug-resistant TB.

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 and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients.

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers.

OBJECTIVE: Two open-label, randomized, cross-over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate. METHODS: Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co-administration of etravirine with tenofovir disoproxil fumarate on either days 1-8 or days 9-16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h. RESULTS: The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration-time curve from 0 to 12 h (AUC(12 h)) for etravirine co-administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61-0.79) and 0.81 (0.75-0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC(24 h) was 1.16 (1.09-1.23) in Study 1 and 1.15 (1.09-1.21) in Study 2. CONCLUSIONS: These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co-administered.

Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study.

BACKGROUND AND OBJECTIVES: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r. METHODS: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed. RESULTS: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated. CONCLUSION: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r.