A Phase I, open-label, randomized, crossover study in healthy subjects to evaluate the bioavailability of, and the food effect on, a pomalidomide oral liquid suspension

Abstract

ObjectiveThe aim of this study was to evaluate the bioavailability of a pomalidomide oral liquid suspension relative to the commercial capsule formulation and to assess the food effect on the pomalidomide oral liquid suspension when administered as a single 4 mg dose.MethodsThis was an open-label, randomized, three-period, two-sequence crossover study in healthy subjects consisting of a screening phase, a baseline assessment phase, a treatment phase with three periods, and a follow-up phone call phase. Blood samples for pharmacokinetics (PK) assessment were collected up to 48 h postdose during each treatment period. Safety was evaluated throughout the study.ResultsPomalidomide exposures were comparable in healthy subjects administered with a single oral 4 mg dose as the reference capsule or as the test liquid suspension formulations, demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the plasma concentration–time curve calculated from time 0 to the last measurable concentration at time t (AUC0–t), area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞), and peak (maximum) plasma drug concentration (Cmax) were completely contained within the bioequivalence range of 80–125%. Administration of the pomalidomide liquid suspension with a high fat meal resulted in a 3.0 h delay in pomalidomide time to Cmax (tmax) and an ~ 34.5% reduction in Cmax. However, the AUCs were comparable after dose administration with and without food.ConclusionA single oral dose of 4 mg of liquid suspension was bioequivalent to a single oral dose of 4 mg of capsule formulation. There was no clinically relevant impact of food on pomalidomide liquid suspension. Single oral doses of 4 mg pomalidomide were safe and well tolerated when administered as a liquid suspension under fed and fasted conditions or as a capsule under fasted conditions.

Bioequivalence of Pomalidomide Capsules in Fasting and Fed States in Healthy Male Volunteers: A Randomized, Open, Single‐Dose, Biperiodic, Double‐Crossover Study

“…22 A food effect bioavailability study conducted on a POM capsule formulation revealed that the coadministration of POM with high-fat and high-calorie meals delayed t max by 2.5 hours, and that it decreased mean plasma C max and AUC in healthy volunteers by ≈27% and 8%, respectively. 12 These results are consistent with the findings of the present study. Therefore, it can be concluded from this analysis that the mild to moderate differences in AUC and C max observed when POM capsules (4 mg) were administered with food do not appear to influence their efficacy or safety profiles.…”

“…Therefore, POM can be administered with or without food. 12 POM was extensively metabolized (primarily by cytochrome P450 [CYP] 1A2 and CYP3A4, and secondarily by CYP2C19 and CYP2D6), and is still the main circulating component (accounting for ≈70% of circulating radioactivity). [13][14][15] A single dose of 4-mg POM was safe and well tolerated by male subjects with severe, moderate, or mild liver injury.…”

“…Food reduces the absorption rate, not the degree, of POM. Therefore, POM can be administered with or without food 12 …”

An open‐label, phase 1, randomized, three treatments, three‐period, crossover, relative bioavailability study of CC‐292, a potent and orally available inhibitor of bruton tyrosine kinase

“…It is critical to characterize the bioavailability (BA), or the bioequivalence (BE), of medications with different formulations in medicine and pharmaceutical development, as per the global regulatory requirement. 17 FDA guidance of BA and BE studies for orally administered drug products indicates that studies to measure BA and/ or establish BE of a product are important elements in support of investigational new drugs (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs) and their supplements. 18,19 In line with the guidance, the study herein was aimed to evaluate the BA of two newly developed formulation (P01-TAB and P22-CAP) relative to the reference formulation (P01-CAP).…”

Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds

“…Most studies investigated compounds acting on the innate immune system (19 studies) (20-38), followed by compounds w i t h i m m u n o r e g u l a t o r y a c t i v i t y , c l a s s i fi e d i n t o immunomodulatory (cereblon [CRBN] modulators; 14 studies) (39)(40)(41)(42)(43)(44)(46)(47)(48)(49)(50)(51)(52) and mediators of immune cell functions (CCR5 antagonists; 14 studies) (54-59, 61-63, 65-67, 76). All the other compounds were investigated in only one or two HV studies.…”