Clinical Pharmacology in Drug Development最新文献

Gantenerumab, a monoclonal antibody targeting amyloid beta plaques in the brain, reduces plaque accumulation and was developed to slow Alzheimer's disease progression. Results from the pivotal GRADUATE I and II studies evaluating gantenerumab in people with early Alzheimer's disease were announced in 2022. The studies did not meet their primary endpoint of slowing clinical decline. This study evaluated the pharmacokinetics, immunogenicity, and safety of a high concentration liquid formulation of gantenerumab administered subcutaneously as a single dose using an autoinjector (AI) or a disposable syringe (DS). The DS was employed in pivotal clinical trials, while the AI was developed in parallel to ease SC administration. The study aimed to demonstrate bioequivalence (BE) between AI and DS administration in healthy participants, defined by 90% confidence intervals (CIs) for geometric least square (LS) mean ratios being within the 0.80-1.25 range for maximum observed plasma concentration (C_max) and area under the plasma concentration-time curve (AUC). Among the 266 healthy participants, 135 received 255 mg gantenerumab via AI and 131 received 255 mg via DS in a parallel group design. BE between AI and DS SC administration was demonstrated with geometric LS mean ratios (90% CIs) for C_max, AUC_0-inf, and AUC_0-last of 1.078 (1.006, 1.155), 1.053 (0.986, 1.124), and 1.054 (0.992, 1.121), respectively, all within the 0.80-1.25 BE range. Safety findings were consistent with the known safety profile of gantenerumab.

This study evaluated the bioequivalence and safety of two fixed-dose combination (FDC) tablet formulations of metformin/empagliflozin (1000 mg/5 mg) in healthy Chinese subjects. A single-center, open-label, randomized, two-period, two-treatment, and two-sequence crossover study was conducted, enrolling 56 subjects who were assigned to either fasting or fed conditions in a 1:1 ratio. Each subject received both the test and reference formulations, with a 7-day washout period between administrations. Blood samples were collected up to 48 h post-dose, and plasma concentrations of metformin and empagliflozin were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Bioequivalence was assessed based on key pharmacokinetic parameters—C_max, AUC_0–t, and AUC_0–∞—with the geometric least-squares mean ratios of the test to reference formulation falling within the accepted bioequivalence range of 80.00% to 125.00% for all 90% confidence intervals under both fasting and fed states. High-fat meals significantly reduced the C_max of metformin and empagliflozin by approximately 47% and 28%, respectively, and their overall exposure (AUC_0−∞) by approximately 29% and 15%, respectively. No serious adverse events were reported. In conclusion, the test and reference formulations of metformin/empagliflozin FDC tablets were bioequivalent and well-tolerated under both fasting and fed conditions.

Ubrogepant is a calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine with or without aura in adults. The mass balance and metabolism of ubrogepant was evaluated in six healthy male adults administered a single oral dose of [¹⁴C]-ubrogepant 50 mg (∼200 µCi). Overall, the mean total radioactivity recovery was 92.4% (95% CI: 77.8%-107%) of the administered dose, with 82.9% in feces (95% CI: 66.7%-99.1%) and 9.52% in urine (95% CI: 7.78%-11.3%). Ubrogepant was eliminated mainly via metabolism, primarily via biliary/fecal excretion. Approximately 42% and 6% of the dose was excreted as unchanged parent drug in feces and urine, respectively. The major circulating components of drug-related material (DRM) in pooled plasma samples were ubrogepant (55%), M15 (13%), and M20 (3.5%). M15 (glucuronide of methylated catechol) and M20 (glucuronide of mono-oxygenated ubrogepant [M8]) also were the main metabolites in urine, together representing about 2% of DRM. In feces, the main metabolites were the oxidative metabolites M6 (di-oxygenated ubrogepant) and M8, together representing about 29% of DRM. In vitro assays showed that ubrogepant metabolism occurs predominantly via CYP3A4.

Fibrodysplasia ossificans progressiva is a rare, progressive autosomal dominant genetic disease caused by an activin receptor-like kinase 2 (ALK2) mutation with a need for effective prophylactic therapies. This single-center, randomized, double-blind, placebo-controlled study evaluated the pharmacokinetics and safety of DS-6016a, a novel humanized monoclonal anti-ALK2 antibody, in healthy Japanese adults. In each of the 5–1000 mg DS-6016a or placebo single subcutaneous dose cohorts, eight male participants were randomly assigned at a 3:1 ratio. DS-6016a had median times to maximum plasma concentration of 144–240 h and elimination half-lives of 391–844 h. The increase in DS-6016a exposure was greater than dose-proportional across the dose range of 5–1000 mg. The incidence of study drug-related treatment-emergent adverse events (TEAEs) was 17% in the placebo group and 11% across all DS-6016a groups; all were mild and resolved without treatment. No deaths, serious or severe TEAEs, or TEAEs leading to study discontinuation were reported. Ferritin showed a statistically significant dose-dependent decrease from baseline, while serum iron showed no clear dose-dependency. No relationship was observed between DS-6016a dose and the development of anti-drug antibodies. DS-6016a had an acceptable safety profile at single subcutaneous doses of 5–1000 mg.

Antihypertensive drugs are more potent when administered in combinations of two or three different classes of drugs. The objective of this study was to evaluate the pharmacokinetic interaction among amlodipine, losartan, and chlorthalidone. A randomized, open-label, four-sequence, four-period, four-treatment, single-dose study was conducted in healthy Korean male subjects, with oral administrations of two tablets of amlodipine 5 mg, one tablet of losartan 100 mg, one tablet of chlorthalidone 25 mg, or co-administration of all three investigational products. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Twenty-six subjects completed the study. The geometric mean ratios and 90% confidence intervals of C_max and AUC_last, respectively, were 1.0928 (1.0412-1.1469) and 1.0360 (0.9958-1.0778) for amlodipine; 1.1016 (0.9136-1.3284) and 1.1606 (1.0885-1.2375) for losartan; 1.0720 (1.0119-1.1356) and 1.0902 (1.0350-1.1148) for EXP3174 (active metabolite of losartan); and 0.9462 (0.8626-1.0379) and 1.0266 (0.9752-1.0807) for chlorthalidone. All the treatments were well tolerated overall. Besides the slight increase in losartan C_max, the combination therapy did not show clinically significant pharmacokinetic interactions in terms of systemic drug exposure.

Stains and cholesterol absorption inhibitors are frequently co-administered in the management of dyslipidemia. This study evaluated the pharmacokinetic (PK) interaction between atorvastatin and hybutimibe in healthy Chinese subjects. A randomized, open-label, three-treatment, six-period crossover study was conducted involving 24 participants. Subjects received once-daily treatments for 14 days per period (14-day washout): atorvastatin 20 mg, hybutimibe 10 mg, or their combination. Geometric mean ratios (GMRs) and their 90% confidence intervals (CI) were calculated for the maximum plasma concentration (C_max) and the area under the plasma concentration–time curve (AUC) of atorvastatin, hybutimibe, and their metabolites, comparing combination therapy with monotherapy. At steady state, the GMRs (90% CI) for atorvastatin were 89.9 (74.6, 108.2) for C_max and 103.7 (96.0, 112.0) for AUC_0-∞ when administered with or without hybutimibe. For total hybutimibe, the corresponding values were 120.6 (102.4, 142.0) and 105.7 (97.1, 115.2), respectively. Considering the limited PK changes and good safety profiles of both drugs, the interaction between atorvastatin and hybutimibe will likely have no significant clinical impact.

Venanprubart (LY3361237), an agonist antibody to B and T lymphocyte attenuator (BTLA), was developed as a potential treatment for autoimmune disorders, including systemic lupus erythematosus (SLE) and psoriasis. We tested venanprubart in three human Phase 1 safety studies: a single ascending dose (SAD) study in healthy participants (1/2/5/15/50/150 mg subcutaneously, or 150/400 mg intravenously; n = 64), a multiple ascending dose study in patients with SLE (six doses every 2 weeks at 50/150/450 mg subcutaneously; n = 28), and a randomized controlled study in patients with psoriasis (six doses every 2 weeks at 450 mg subcutaneously; n = 24). Key endpoints across studies included safety and tolerability, pharmacokinetics, receptor occupancy of BTLA on B cells, CD4+ T cells, CD8+ T cells, and immunogenicity as measured by treatment-emergent anti-drug antibodies (TE ADA). Venanprubart was well tolerated in healthy participants and in patients with SLE and psoriasis. No participants discontinued treatment due to adverse events, and nearly all treatment-emergent events were mild or moderate. The pharmacokinetic profile of venanprubart was nonlinear. Serum concentrations of venanprubart increased greater than dose proportionally at lower doses, but exposure became more linear after target binding was nearly saturated. Higher doses led to high levels of receptor occupancy on B cells, CD4+, and CD8+ T cells, indicating a high level of target engagement. Irrespective of titer, TE ADA incidence was 79%, 71%, and 71% for healthy participants, patients with SLE, and patients with psoriasis, respectively. ADA titers were lower in the repeat-dose studies compared to the SAD study, especially at higher doses.

This study assessed the effect of high-fat food on pharmacokinetics and safety of amlodipine, benazepril, and benazeprilat in healthy Chinese participants under fasting and fed conditions from a bioequivalence trial. This trial enrolled a total of 92 healthy participants, and there was a significant difference in age between fasting and fed trials (P = .006). These participants received an amlodipine/benazepril capsule containing 5 mg amlodipine and 10 mg benazepril each period with a 21-day washout under fasting or fed conditions. Twenty-four blood samples were obtained from baseline to 168 h after drug administration for pharmacokinetic analyses. The plasma concentrations of amlodipine, benazepril, and benazeprilat were determined by a validated liquid chromatography-tandem mass spectrometry method. After controlling for age, analysis of covariance (ANCOVA) or Quade’s ANCOVA of pharmacokinetic results indicated that a high-fat meal did not significantly influence the primary pharmacokinetic parameters of amlodipine, benazepril, and benazeprilat, except for the maximum plasma concentration (C_max) and time to reach maximum plasma concentration (T_max) for benazepril and benazeprilat. The high-fat food decreased C_max of benazepril by 64.1% and C_max of benazeprilat by 30.8%, and increased T_max of benazepril by 408.2% and T_max of benazeprilat by 167.8% The incidence of most frequently observed AE of hypotension was significantly different (P = .014, risk ratio = 2.286, and 95% confidence intervals 1.103 to 4.737) under fasting and fed conditions. It suggested that high-fat food containing 800 to 1000 kcal might be the risk factor for healthy Chinese participants taking amlodipine/benazepril capsules.

Grapefruit juice (GFJ) is a known inhibitor of intestinal cytochrome P450 3A (CYP3A) metabolism leading to increased exposure to CYP3A substrates such as tacrolimus. The extended-release tacrolimus formulation Envarsus (LCPT) exhibits prolonged absorption throughout the entire GI tract. Although a clinically significant drug–drug interaction occurs with immediate-release tacrolimus formulations, this has not been evaluated with extended-release formulations. This study assessed the impact of GFJ on LCPT in adult kidney transplant patients. Eleven adult kidney transplant recipients on a stable dose of LCPT were enrolled in a randomized crossover study. Participants were administered either GFJ or water during each pharmacokinetic visit, with midazolam used as a positive control. A washout period of 2–4 weeks was included between visits. Tacrolimus concentrations were determined using validated LC-MS/MS methods. Tacrolimus AUC_0–24 was 28% higher with GFJ (GMR = 1.28, 90% CI 1.12–1.44) and C_max was 73% higher (GMR = 1.73, 90% CI 1.46–2.00) compared to control. GFJ exhibited a clinically meaningful interaction with LCPT. However, the magnitude appears less than those reported with immediate-release formulations, suggesting the extended absorption profile of LCPT may affect susceptibility to drug interactions in the intestine.