Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1. METHODS: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires. RESULTS: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers. CONCLUSION: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04006704.

Bioequivalence of a Pediatric Fixed-Dose Combination Tablet Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Compared With Coadministration of the Separate Agents in Healthy Adults: An Open-Label, Randomized, Replicate Crossover Study.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a fixed-dose combination (FDC) for the treatment of HIV-1 infection in adults and adolescents weighing 40 kg or greater. This Phase 1, randomized, open-label, 2-treatment, 2-sequence, 4-period replicate crossover study (NCT04661397) evaluated the pivotal bioequivalence of a pediatric D/C/F/TAF 675/150/200/10-mg FDC compared with coadministration of the separate commercially available formulations in healthy adults under fed conditions. During each period, participants received either a single oral dose of D/C/F/TAF 675/150/200/10-mg FDC (test) or a single oral dose of darunavir 600 and 75 mg, cobicistat 150 mg, and emtricitabine/tenofovir alafenamide 200/10-mg FDC (reference). Thirty-seven participants were randomly assigned to one of 2 treatment sequence groups: test-reference-reference-test or reference-test-test-reference, with 7 days or more washout between periods. The 90% confidence intervals of the geometric mean ratios for maximum plasma concentration, area under the concentration-time curve from time zero to last measurable concentration, and area under the concentration-time curve extrapolated to infinity for darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fell within conventional bioequivalence limits (80%-125%). No Grade 3/4 adverse events, serious adverse events, or deaths occurred. In conclusion, administration of D/C/F/TAF 675/150/200/10-mg FDC was bioequivalent to coadministration of the separate commercially available formulations.

In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats.

This study evaluated in vitro and in vivo drug release of bedaquiline from in situ forming gels (ISGs) containing 200 mg eq./g bedaquiline fumarate salt prepared with four different grades of poly(d,l-lactide) (PDLLA) or poly(d,l-lactide-co-glycolide) (PLGA) with a lactide/glycolide ratio of 50/50 or 75/25 and acid (A) or ester (E) end-capping in N-methyl-2-pyrrolidone at a polymer/solvent ratio of 20/80% (w/w). Mean in vitro drug release in 0.05 M phosphate buffer pH 7.4 with 1% (w/v) sodium lauryl sulphate was 37.3, 47.1, 53.3, and 62.3% within 28 days for ISGs containing PLGA5050A, PDLLA, PLGA7525A, and PLGA7525E, respectively. The data suggested that drug release was primarily controlled by precipitated drug redissolving, rather than polymer erosion. In vivo pharmacokinetic profiles after subcutaneous injections in rats were comparable for all ISGs (mean half-lives (t1/2) ranged from 1411 to 1695 h) and indicated a sustained drug release when compared to a solution of bedaquiline fumarate salt in polyethylene glycol 400/water 50/50% (v/v) (mean t1/2 of 895 h). In conclusion, PLGA or PDLLA-based ISGs have shown potential for parenteral sustained delivery of bedaquiline, suggesting further preclinical and clinical studies. From a formulation point of view, this case example highlights the importance of the interplay between drug solubility in biological media and dissolution of drug precipitates, which, in addition to the incorporation of diffusion controlling polymers, governs the release of the active drug.

Clinical pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-54175446, a brain permeable P2X7 antagonist, in a randomised single-ascending dose study in healthy participants.

BACKGROUND: Central nervous system-derived interleukin-1ß plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1ß. AIMS: This first-in-human study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants. METHODS: The study had three parts: an ascending-dose study in fasted participants (0.5-300 mg JNJ-54175446); an ascending-dose study in fed participants (50-600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effective concentration (EC)50 (105 ng/mL) and EC90 (900 ng/mL) values for central nervous system P2X7 receptor binding. RESULTS: Seventy-seven participants received a single oral dose of JNJ-54175446 ( n=59) or placebo ( n=18). Area under the curve of concentration time extrapolated to infinity (AUC∞) increased dose-proportionally; maximum concentration (Cmax) of plasma (Cmax,plasma) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest Cmax,plasma reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 Cmax in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound Cmax,plasma and Cmax,CSF were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3'-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1ß release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC)50:82 ng/mL; 95% confidence interval: 48-94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%). CONCLUSION: Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1ß release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.

Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis.

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data of a solution and suspension formulation, would facilitate informed decision making on the clinical formulation development strategy. In addition, the predictive value of (in vitro) selection criteria, such as solubility, human permeability, and/or a clinical dose number (Do), were evaluated, potentially reducing additional supporting formulation bioavailability studies in animals. The absolute ( Fabs,sol) and relative ( Frel, susp/sol) bioavailability of an oral solution and suspension, respectively, in rat or dog and the anticipated BCS classification were analyzed for 89 Janssen compounds with 28 of these having Frel,susp/sol and Fabs,sol in both rat and dog at doses around 10 and 5 mg/kg, respectively. The bioavailability outcomes in the dog aligned well with a BCS-like classification based upon the solubility of the active pharmaceutical ingredient (API) in biorelevant media, while the alignment was less clear for the bioavailability data in the rat. A retrospective analysis on the clinically tested formulations for a set of 12 Janssen compounds confirmed that the previously proposed animal bioavailability-based decision tree facilitated decisions on the oral formulation type, with the dog as the most discriminative species. Furthermore, the analysis showed that based on a Do for a standard human dose of 100 mg in aqueous and/or biorelevant media, a similar formulation type would have been selected compared to the one suggested by the animal data. However, the concept of a Do did not distinguish between solubility enhancing or enabling formulations and does not consider the API permeability, and hence, it produces the risk of slow and potentially incomplete oral absorption of an API with poor intestinal permeability. In cases where clinical dose estimations are available early in development, the preclinical bioavailability studies and dose number calculations, used to guide formulation selection, may be performed at more relevant doses instead of the proposed standard human dose. It should be noted, however, that unlike in late development, there is uncertainty on the clinical dose estimated in the early clinical phases because that dose is usually only based on in vitro and/or in vivo animal pharmacology models, or early clinical biomarker information. Therefore, formulation strategies may be adjusted based on emerging data supporting clinical doses. In summary, combined early information on in vitro-assessed API solubility and permeability, preclinical suspension/solution bioavailability data in relation to the intravenous clearance, and metabolic pathways of the API can strengthen formulation decisions. However, these data may not always fully distinguish between conventional (e.g., to be taken with food), enhancing, and enabling formulations. Therefore, to avoid overinvestment in complex and expensive enabling technologies, it is useful to evaluate a conventional and solubility (and/or permeability) enhancing formulation under fasted and fed conditions, as part of a first-in-human study or in a subsequent early human bioavailability study, for compounds with high Do, a low animal Frel,susp/sol, or low Fabs,sol caused by precipitation of the solubilized API.