Pharmacokinetics, Safety, and Tolerability of Once-Daily Darunavir With Cobicistat and Weekly Isoniazid/Rifapentine.

BACKGROUND: Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP. METHODS: This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5-19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models. RESULTS: Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration-time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48-72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL). CONCLUSIONS: Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided.

Bayesian model-guided antimicrobial therapy in pediatrics.

Antimicrobials have transformed the practice of medicine, making life-threatening infections treatable, but determining optimal dosing, particularly in pediatric patients, remains a challenge. The lack of pediatric data can largely be traced back to pharmaceutical companies, which, until recently, were not required to perform clinical testing in pediatrics. As a result, most antimicrobial use in pediatrics is off-label. In recent years, a concerted effort (e.g., Pediatric Research Equality Act) has been made to fill these knowledge gaps, but progress is slow and better strategies are needed. Model-based techniques have been used by pharmaceutical companies and regulatory agencies for decades to derive rational individualized dosing guidelines. Historically, these techniques have been unavailable in a clinical setting, but the advent of Bayesian-model-driven, integrated clinical decision support platforms has made model-informed precision dosing more accessible. Unfortunately, the rollout of these systems remains slow despite their increasingly well documented contributions to patient-centered care. The primary goals of this work are to 1) provide a succinct, easy-to-follow description of the challenges associated with designing and implementing dose-optimization strategies; and 2) provide supporting evidence that Bayesian-model informed precision dosing can meet those challenges. There are numerous stakeholders in a hospital setting, and our intention is for this work to serve as a starting point for clinicians who recognize that these techniques are the future of modern pharmacotherapy and wish to become champions of that movement.

The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults.

ANS-6637, a pro-drug of GS-548351, is a selective, reversible inhibitor of aldehyde dehydrogenase isoform 2 under development as an anticraving agent for the treatment of substance use disorders. In vitro testing indicates that GS-548351 is an inhibitor and inducer of cytochrome P450 family 3, subfamily A (CYP3A). In this phase 1 single-center, open-label, fixed-sequence drug-drug interaction study we assessed the impact of steady-state GS-548351 on single-dose pharmacokinetics of midazolam, an index substrate for CYP3A. Twelve healthy volunteers received 600 mg of ANS-6637 by mouth daily from study days 3 to 8 and a single 5-mg oral dose of midazolam on days 1 and 8. Pharmacokinetic samples were collected over 24 hours on days 1 and 8, then analyzed using liquid chromatography-tandem mass spectrometry. The prespecified no-effect range for the 90% confidence interval (CI) of the geometric mean ratio (GMR) of midazolam coadministered with ANS-6637 (day 8) compared with midazolam alone (day 1) was 0.7-1.43. There was an increase in midazolam AUC0-∞ (GMR [90%CI]) that was within the no-effect range (1.26 [1.12-1.425]) and an increase in midazolam Cmax that was outside the range (1.22 [1.03-1.45]). The AUC0-∞ (1.08 [0.91-1.27]) and Cmax (0.95 [0.75-1.2]) of 1-hydroxymidazolam, the primary metabolite of midazolam, were also within the no-effect range. A single grade 3 adverse event (alanine aminotransferase elevation) was identified and resolved following discontinuation of the study drug. Overall, multidose ANS-6637 was well tolerated and did not alter the PK of midazolam beyond a small increase in AUC0-∞ that is unlikely to be clinically significant.