Clinical Pharmacology in Drug Development最新文献

Long-acting cabotegravir is approved for HIV treatment and prevention. To guide management of dosing deviations and interruptions, concentration-time profiles for monthly and every 2 months regimens were simulated using a population pharmacokinetic (PPK) model. Adequate exposure was defined as trough concentration (C_tau) >0.45 µg/mL (observed 5th percentile of first C_tau in pivotal studies) in >95% of subjects and maximum concentration (C_max) <13.1 µg/mL (highest observed median steady-state C_max in previous studies) in >50% of subjects. Simulations showed: (1) median C_max remained ≤6.35 µg/mL after doubled doses; (2) C_tau was suboptimal after half dose at first injection but recovered with a corrective dose; (3) injection delays ≤7 days maintained adequate C_tau, while longer delays caused extended low-exposure periods (≤23 days for 1-month delay, ≤83 days for 3-month delay); (4) reinitiating loading dose after delays >1 month led to higher exposure than continuing injections and may mitigate efficacy loss and resistance risks; and (5) oral bridging (30 mg daily) maintained adequate exposure during delays. Recommended strategies include no action for higher-than-planned doses, corrective dosing for lower-than-planned doses, strict adherence to schedule, reinitiating the loading dose after delays >1 month, and oral bridging. These findings were incorporated into product labeling and can inform next-generation cabotegravir and other long-acting agent development.

Armodafinil, the R-enantiomer of modafinil that promotes wakefulness, was studied regarding its pharmacokinetics and safety in healthy Chinese subjects after multiple-dose oral administration (200 mg daily for 7 days). Twelve subjects participated in this single-center, self-contrast study. The plasma concentrations of armodafinil and its metabolites (R-modafinil acid and modafinil sulfone) were measured by ultra-performance liquid chromatography–tandem mass spectrometry, and drug safety was evaluated during the study. The steady-state accumulation ratio of armodafinil was 1.5, and its metabolites also accumulated with ratios of 1.3 and 7.8, respectively. Although the mean steady-state half-life was similar to that after a single dose, the area under the concentration–time curve, maximum plasma concentration, and clearance of armodafinil changed significantly after multiple dosing. The drug was safe with no serious adverse events, yet fever occurred in 6 subjects, which was not reported before. Modafinil sulfone had significant accumulation, implying the need for further study on its central nervous system–activating properties in Chinese patients.

HT-101, a liver-targeted N-acetylgalactosamine-conjugated ribonucleic acid interference therapeutic, exhibits promising potential for the treatment of chronic hepatitis B virus infection. This randomized, double-blind, placebo-controlled, and single-ascending-dose Phase Ia study included 50 healthy volunteers. Regarding methods, 2 subjects received a single subcutaneous dose of HT-101 at 25 mg, while 48 volunteers were randomized (6:2 active:placebo) in the remaining 6 cohorts to receive a single subcutaneous dose of HT-101 (50-800 mg) or placebo. Afterward, serial blood samples were obtained for pharmacokinetic determination across a 48-hour postdose period. Safety assessments included clinical laboratory measures, vital signs, and 12-lead electrocardiogram before and after dosing. As a result, plasma pharmacokinetics characterized by functional antisense strand revealed a median time to peak plasma concentration of 2.5-6.0 hours, and a short median plasma half-life of 2.50-6.14 hours. It is underlined that peak and total plasma exposure to HT-101 increased in a slightly greater-than-dose-proportional manner following 25-800 mg administered subcutaneously. Moreover, a single dose of HT-101 at 25-800 mg was safe and well tolerated in healthy Chinese volunteers. These data can support further clinical development of HT-101 for hepatitis B virus infection treatment.

Aildenafil citrate is a novel and potent phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction (ED). This study evaluates the pharmacokinetics and bioequivalence of 2 formulations of aildenafil citrate tablets (30 and 60 mg) in healthy Chinese male subjects under both fasting and fed conditions. A single-center, randomized, open-label, 2-period crossover design was employed, with 78 participants enrolled, including 30 in the fasting condition and 48 in the fed condition. Blood samples were collected at multiple time points for pharmacokinetic analysis, which included C_max, AUC_0-t, and AUC_0-∞ as the primary parameters. The results demonstrated that the pharmacokinetic profiles of the test and reference formulations were comparable in both the fasting and fed states, with 90% confidence intervals for the geometric mean ratios of C_max, AUC_0-t, and AUC_0-∞ falling within the 80%-125% range, confirming bioequivalence. Although food intake slightly delayed the time to peak concentration and reduced the absorption rate, it did not significantly affect the overall bioavailability. Both formulations were well tolerated, with adverse events being mild and resolving spontaneously. This study provides evidence supporting the bioequivalence of the 2 aildenafil citrate formulations and their interchangeability for clinical use in treating ED.

The objective of this study was to evaluate the pharmacokinetics and safety of a generic and a branded reference formulation of ibuprofen extended-release capsules. Bioequivalence between the 2 products was assessed through a clinical trial conducted in healthy Chinese volunteers. The study was divided into 2 groups: fasting and postprandial. Thirty-two volunteers were enrolled in the fasting group and 24 in the postprandial group. Participants in each group were randomly assigned to receive either the generic (test) or branded (reference) product. Following the first dosing cycle, a 7-day washout period was observed. Afterward, subjects crossed over to the alternate treatment and completed a second cycle. Pharmacokinetic parameters were determined using plasma concentration-time profiles. These included the area under the plasma concentration-time curve during the dosing interval (AUC_0-t), the AUC extrapolated to infinity (AUC_0-∞), the maximum observed plasma concentration (C_max), the time to reach C_max (t_max), and the elimination half-life (t₁/₂). The results demonstrated that the generic and reference ibuprofen extended-release capsules were bioequivalent in healthy Chinese volunteers under both fasting and postprandial conditions.

Ulipristal acetate (UPA) is indicated for the treatment of moderate to severe uterine fibroids in adult women of reproductive age who are candidates for surgical intervention. A single-center, randomized, open-label, 2-period crossover study was conducted in 46 healthy female subjects under both fasting and postprandial conditions. Blood samples were collected for pharmacokinetic analysis following the oral administration of a 5-mg dose of UPA. Plasma concentrations were quantified using liquid chromatography-tandem mass spectrometry. The 90% confidence intervals of the ratio of geometric mean of maximum concentration, area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurable concentration, AUC from time 0 to infinity of UPA, and monodemethyl-UPA all fell within the bioequivalence range of 80%-125% under both fasting and postprandial conditions. In this study, coadministration oral UPA 5 mg with a high-fat meal resulted in a maximum concentration that was approximately 25% lower, a delayed time to reach maximum concentration (from a median of 0.5-3 hours) than with the fasting state, and an AUC from time 0 to infinity that increased by a factor of 1.58-1.85. Similar results were observed for the active metabolite (monodemethyl-UPA). All adverse events recorded during the study were of mild intensity, and no serious adverse events were observed. Both preparations showed good safety and tolerability. No data are available on the clinical importance of the food effect. Until such data becomes available, treating physicians should be aware of the increase in systemic exposure based on fasting versus postprandial conditions and plan dosage regimens accordingly.

Topical diclofenac diethylamine (DDEA) gels relieve pain while maintaining low diclofenac systemic concentrations in nontarget tissues. Characterizing diclofenac systemic exposure remains a mandated element in the development of topical diclofenac products. Two Phase I, randomized, open-label, multiple-dose, crossover studies were conducted with the objective of assessing the systemic bioavailability of DDEA topical gels and oral diclofenac tablets in healthy volunteers. In addition to evaluating bioavailability, safety and tolerability were also examined. In Study 1, participants applied DDEA 2.32% gel twice daily (with/without semiocclusive bandage) or DDEA 1.16% gel 4 times daily (no bandage) to 1 ankle. In Study 2, participants applied DDEA 2.32% gel twice daily to 1 knee or both knees. Both studies compared topical treatments with oral diclofenac sodium tablets 50 mg 3 times daily. In Study 1, similar diclofenac bioavailabilities were observed for DDEA 1.16% gel 4 times daily and DDEA 2.32% gel twice daily; the presence of a semiocclusive bandage had a minimal impact on bioavailability. In Study 2, diclofenac bioavailability was proportional to the number of DDEA 2.32% gel application sites. Systemic diclofenac concentration for topical application was significantly lower (up to 150- and 75-fold) compared to oral treatments and was well tolerated. These studies contribute to the benefit–risk assessment of topical DDEA.

Imlunestrant (LY3484356) is a next-generation orally bioavailable selective estrogen receptor degrader being investigated for the treatment of estrogen receptor–positive advanced breast and endometrial cancers. This Phase 1, open-label, 2-part study evaluated the disposition and absolute bioavailability of [¹⁴C]-imlunestrant in 16 US-based healthy women (aged 36-65 years) of non–childbearing potential. Part 1 participants (N = 8) received an oral dose of 400-mg [¹⁴C]-imlunestrant solution (100 µCi). Part 2 participants (N = 8) received an oral dose of 2 × 200-mg imlunestrant tablets followed by approximately 45 µg [¹⁴C]-imlunestrant (approximately 1 µCi) given as a 15-minutes infusion 4 hour later. Blood, fecal, and urine samples were collected. Total radioactivity was primarily eliminated in feces (97.3%) with trace amounts recovered in urine (0.278%), suggesting minimal renal clearance. Imlunestrant accounted for most of the radioactive dose in feces (61.8%), followed by metabolite M2 (20.9%), metabolites M5 + M10 (coeluted), M7, M8, M9, and M11 (5.1% or less for each). Absolute bioavailability of imlunestrant after oral administration relative to intravenous administration was 10.9% based on dose-normalized area under the concentration–time curve from time zero to infinite time. Imlunestrant was well tolerated as an oral solution or as a tablet/intravenous dose. Eight participants reported mild/moderate treatment-related adverse events that resolved by the end of the study.

Clascoterone is an androgen receptor inhibitor approved for the treatment of acne vulgaris in patients 12 years of age and older. Here, we report results of 5 phase 1 studies that assessed the pharmacokinetics (PK), safety, and skin irritation and sensitization potential of clascoterone cream 1% in healthy participants and patients with acne. Studies CB-03-01/02 (EudraCT: 2007-005064-28) and CB-03-01/04 (n = 24 each) assessed PK in healthy participants. Study 171-7151-203 (n = 8) assessed steady-state PK in patients with acne. Studies CB-03-01/05 (n = 36) and CB-03-01/32 (n = 250) assessed skin irritation and sensitization potential, respectively, in healthy participants. Systemic exposure to clascoterone was low after repeated daily application for up to 42 days of treatment. Clascoterone was excreted in urine as conjugated esters at a ≤1% fraction of the administered dose. Adverse events and local skin reactions were generally mild/moderate and reversible. No clinically relevant changes were observed in laboratory tests and vital signs. Skin irritation and sensitization with clascoterone treatment were minimal. Phase 1 study findings supported low systemic absorption of clascoterone and a favorable safety profile after topical application of clascoterone cream 1%, with no evidence of irritation or sensitization.