Clinical Pharmacology in Drug Development最新文献

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.

The study aimed to evaluate the pharmacokinetics, bioequivalence, and safety of domestic diclofenac sodium sustained-release tablets (0.1 g) and a reference formulation in healthy Chinese subjects. Two independent trials (fasting and fed conditions) were conducted with a single-center, randomized, open-label, single-dose, two-sequence, four-period, fully replicated design. Plasma diclofenac concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated via a noncompartmental model using Phoenix WinNonlin software (version 7.0). Multivariate analysis of variance was performed on the natural logarithm-transformed pharmacokinetic parameters (C_max, AUC_0–t, and AUC_0–∞) of the test and reference formulations using a mixed linear model. Average bioequivalence (ABE) was used for assessment if the within-subject variability (S_WR) of the reference formulation was < 0.294; otherwise, reference-scaled average bioequivalence (RSABE) was applied. In the fasting trial, the 90% confidence intervals (CIs) for the geometric least-squares mean ratios of C_max, AUC_0–t, and AUC_0–∞ (test/reference) were 82.35%−106.55%, 99.77%−105.78%, and 99.87%−105.40%, respectively. In the fed trial, the corresponding 90% CIs were 82.07%−101.66%, 93.00%−102.02%, and 99.38%−104.51%, respectively. Seventeen adverse events (AEs) were recorded in 10 subjects (41.7%) in the fasting trial and 17 AEs in 12 subjects (40.0%) in the fed trial. All AEs were grade 1 (mild). These results demonstrate that the test and reference diclofenac sodium sustained-release tablets are bioequivalent and well tolerated in healthy Chinese subjects, supporting their clinical interchangeability.

This first-in-human phase I trial evaluated RL001, a self-emulsifying soft-capsule abiraterone developed to overcome the low bioavailability and food sensitivity associated with the 1000-mg Zytiga tablet that is used with prednisone according to NCCN guidelines. Plasma concentrations were quantified by LC-MS/MS and modeled in Phoenix WinNonlin 8.1 and SAS; GeoMean confidence intervals compared pharmacokinetics. Against 1000-mg abiraterone acetate tablet, the 200 mg RL001 achieved abiraterone C_max GMR >125% and AUC_0-t, AUC_0-∞ 80–125%, indicating higher bioavailability and enabling a lower therapeutic dose. The GMR of prednisone and its metabolite remained within 80%–125%, confirming no interaction. Fed/fasted exposure ratios stayed around 80% for AUC and <80% for C_max, eliminating food spikes. Hyperbilirubinemia and hypertriglyceridemia were significantly less frequent. The abiraterone self-emulsifying soft capsule represents a safer and more convenient therapeutic option in the management of prostate cancer.

The objective of this study is to evaluate the safety, pharmacokinetics, and pharmacodynamics of LP-001 injection in healthy Chinese subjects. This was a single-center, double-blind, randomized, dose-escalation study. Fifty-six healthy adults were enrolled and randomly assigned to receive LP-001 or matched placebo. A total of 156.0 drug related adverse events occurred during treatment in 38 subjects who received LP-001 injection. The main events were grade 1 serum iron reduction and elevated triglycerides, which were considered related to the drug's erythropoietic effect and reversible. Pharmacokinetic exposure increased with dose (0.5–50 mcg·kg⁻¹), but the increase in maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC) was greater than the dose ratio (non-linear). Pharmacodynamics showed dose-dependent increases in hemoglobin (Hb), red blood cell count (RBC), hematocrit (HCT), and reticulocyte count (Rtc). The pharmacodynamic indicators in the 15 and 30 mcg·kg⁻¹ multiple-dose groups were significantly higher than those in the placebo group, and the increase in RBC count was more pronounced in the 30 mcg·kg⁻¹ group. LP001, a long-acting rhEPO, was safe and well-tolerated at all doses in this Phase I study. These findings support its continued development as a treatment for myelodysplastic syndromes (MDS).

Milvexian is an oral factor XIa inhibitor in development for prevention of major thromboembolic conditions. This randomized, double-blind, placebo- and positive-controlled, multiple-dose, four-period crossover study assessed the cardic safety of milvexian (including effects on the QT interval of the electrocardiogram), with a supporting in vitro component. Sixty-six participants were enrolled. In each treatment period, participants received milvexian (100 or 200 mg) or placebo every 12 h for 4 days. A single-dose moxifloxacin (400 mg) served as a positive control. Electrocardiographs and time-matched pharmacokinetic samples were collected during each period. In mixed-effects models, the upper limit of the two-sided 90% confidence interval for the least squares means for change from baseline QTc (Fridericia [QTcF], as the primary correction method) for milvexian versus placebo (ΔΔQTc) was ˂10 ms at all time points after each milvexian regimen. In addition, there was no apparent relationship between ΔΔQTcF and plasma milvexian concentrations. Moxifloxacin response confirmed assay sensitivity. Milvexian inhibited human ether-a-go-go-related gene potassium, sodium, and L-type calcium ion channel currents with weak-to-moderate potency at concentrations exceeding the highest mean unbound maximum plasma concentrations of TQT study participants. Milvexian regimens were safe and well tolerated. These data indicate that milvexian does not prolong the QTc interval at clinically relevant concentrations.

SGR-1505 is a novel small-molecule inhibitor of MALT1, a key mediator of NF-κB signaling implicated in the pathogenesis of B-cell malignancies. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SGR-1505 in healthy volunteers. In this four-part, open-label study, 73 participants received single or multiple oral doses of SGR-1505 (25–225 mg). A food effect study assessed SGR-1505 exposure with and without a high-calorie, high-fat meal. The CYP3A4 drug–drug interaction potential of SGR-1505 was evaluated by co-administration with posaconazole, a strong CYP3A4 inhibitor. SGR-1505 was rapidly absorbed (median T_max 2–4 h) with a dose-proportional increase in exposure up to 100 mg. Twice daily dosing at 100 mg over 10 days resulted in a 1.6-fold increase in both C_max and AUC and a 2.5-fold increase in C_trough compared to once daily dosing at 150 mg. A high-fat, high-calorie meal increased SGR-1505 C_max 1.6-fold and AUC 1.3-fold compared to the fasted state. Co-administration with posaconazole increased SGR-1505 exposure 3-fold. SGR-1505 inhibited ex vivo stimulated T-cell derived IL-2 production in a concentration-dependent manner. Most adverse events were mild. Asymptomatic, reversible indirect hyperbilirubinemia occurred, consistent with inhibition of UGT1A1. SGR-1505 was well-tolerated and exhibited favorable pharmacokinetic and pharmacodynamic properties, supporting further clinical development.