Clinical Pharmacology in Drug Development最新文献

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.

A pediatric-friendly powder for oral suspension (PfOS) of tovorafenib, a type II RAF inhibitor, was developed for patients with difficulty swallowing tablets. This open-label, randomized, phase 1 study (QSC205140) evaluated the taste/palatability of PfOS formulations (n = 12), the relative bioavailability of the PfOS versus tablet formulation, and the food effect on tablets (n = 12) in healthy participants. Tovorafenib was initially administered at 300 mg and reduced to 100 mg due to musculoskeletal adverse events (AEs). The addition of sweetener and/or flavoring improved taste/palatability. Geometric mean ratios (90% confidence interval) of dose-corrected peak plasma drug concentration (C_max/D) and area under the plasma concentration–time curve from time zero to the last measurable concentration (AUC_0-last/D) between the PfOS and tablet formulations were 96% (83%-111%) and 104% (95%-115%), respectively. Compared with fasted administration, administration of the tablet with food resulted in a 2-3.5-hours delay in time to C_max, and a 20% reduction in C_max/D with no change in AUC_0-last/D. Four severe and 7 moderate AEs occurred with 300 mg of tovorafenib. All remaining AEs, reported with both 100 mg and 300 mg, were mild. These data suggest that tovorafenib PfOS and tablet formulations are comparable, and that the tablet can be administered with or without food.

Obexelimab is an investigational, bifunctional, nondepleting, humanized monoclonal antibody that binds CD19 and FcγRIIb to inhibit B-lineage cell activity. This study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of obexelimab administered intravenously in healthy volunteers (n = 48; single doses of 0.03-10.0 mg/kg) and patients with rheumatoid arthritis (n = 57; 6 doses of 0.3-10.0 mg/kg every 2 weeks). After single-dose administration, obexelimab exhibited nonlinear PK consistent with target-mediated drug disposition, with terminal elimination half-life increasing from 34.4 to 102 hours and clearance decreasing from 42.4 to 16.4 mL/day/kg across the dose range. Multiple dosing every 2 weeks demonstrated more linear PK with low accumulation (8%-22% increase in area under the concentration–time curve). Complete CD19 receptor occupancy occurred rapidly across doses, while CD20⁺ B-cell counts decreased to approximately 50% of baseline with dose-dependent recovery (15-61 days after single doses). Immunomodulatory effects included partial suppression of CD86 expression and significant reduction in antigen-specific antibody responses. Antidrug antibodies were detected in 44.4% and 17.5% of participants in single- and multiple-dose studies, respectively, with neutralizing antibodies in 0% and 2.5%. Obexelimab was generally well-tolerated, primarily mild-to-moderate gastrointestinal events occurring more frequently than with placebo. These results support further development of obexelimab for autoimmune disorders.

The aim of this study was to evaluate the bioequivalence and safety of a single application of crisaborole ointment to test formulation and reference formulation in healthy subjects under fasting conditions. A total of 32 subjects were included and divided into 2 groups (test-reference; reference-test). A single-center, single-dose, 2-formulation, 2-period, 2-sequence, open, randomized, and crossover trial design was adopted. Eligible healthy subjects were applied with the test preparation (domestic crisaborole ointment) or the reference preparation (original crisaborole ointment), followed by a 7-day washout period. Blood samples were collected at predetermined time points before and after administration. After the development and verification of the blood concentration detection method for this study, the third-party supplier used liquid chromatography-tandem mass spectrometry to determine the plasma concentration of crisaborole and used SAS Version 9.4 software to calculate the pharmacokinetic parameters and evaluate the bioequivalence. In this study, the 90% confidence intervals of the geometric mean ratios of maximum concentration, area under the concentration-time curve over the dosing interval, and area under the concentration-time curve from time 0 to infinity were within the acceptable range (80%-125%). During the study, 5 subjects had 8 adverse events, and no serious adverse events were reported. In this study, the tested formulation of crisaborole ointment is bioequivalent to the reference formulation, and the safety is comparable.

Sodium valproate, a broad-spectrum antiseizure medication of the fatty acid derivative class, was investigated in this study. The trial was designed as a single-center, open-label, randomized, 2-treatment, 4-period, 2-sequence crossover study conducted among healthy Chinese subjects. The objective was to evaluate the pharmacokinetic properties and bioequivalence of a novel generic 0.2g sodium valproate tablet and the branded reference product under fasting (n = 28) and fed (n = 28) conditions, with a 14-day washout period between dosing periods. Blood samples were collected at predefined time points within 72 hours after dosing, and plasma valproic acid concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry method. The results demonstrated comparable pharmacokinetic profiles between the formulations, with the 90% confidence intervals for both maximum plasma concentration and area under the concentration-time curve falling entirely within the 80%-125% bioequivalence acceptance range. Additionally, although food coadministration reduced maximum plasma concentration and delayed time to maximum concentration, area under the concentration-time curve remained unaffected. Regarding safety, neither formulation caused serious adverse events, and both exhibited similar safety profiles. These findings indicate that the generic sodium valproate tablet is bioequivalent to the reference product, with both formulations showing consistent bioequivalence and safety.