Journal of clinical pharmacology最新文献

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG₂₀₀₀ -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.

Mogamulizumab is a humanized monoclonal antibody against C-C chemokine receptor 4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of cutaneous T-cell lymphoma (CTCL). The exposure-response relationships for efficacy (progression-free survival [PFS] and overall response rate [ORR]) and safety (the 5 most common treatment-related adverse events by Medical Dictionary for Regulatory Activities [MedDRA] System Organ Class) for 184 patients with CTCL treated with mogamulizumab in a large, registrational clinical trial. Exposure metrics were area under the serum mogamulizumab concentration-time curve over the dose interval at steady state (AUC_ss ) and minimum serum mogamulizumab concentration after the first dose (C_min,1st ). PFS by investigator assessment, the primary efficacy objective, and PFS and ORR by independent review were not correlated with exposure metrics; however, there was a statistically significant positive relationship between a secondary objective, ORR by investigator assessment, and AUC_ss (P = .0168). The frequency of treatment-related adverse events was not related to exposure metrics (C_min,1st or AUC_ss ) for any of the MedDRA System Organ Classes examined. Of the covariates that were found to have a statistically significantly effect on the population PK model (ie, albumin, aspartate aminotransferase, body surface area, mild to moderate hepatic impairment, and sex), none was found to impact efficacy or safety, indicating that there is no need to modify dose on the basis of these parameters.

Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin C_max , AUC_last , and AUC_0-∞ with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the "no-effect" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUC_last and AUC_last ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.

The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15-day regimen of upadacitinib 30 mg once daily (extended-release formulation). Serial blood samples and 12-hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration-time curve from time 0 to infinity (AUC_inf ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 (0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUC_inf ratio and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.

Cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATL) are rare non-Hodgkin lymphomas commonly expressing C-C chemokine receptor 4 (CCR4). Mogamulizumab is a humanized monoclonal antibody against CCR4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of CTCL. Pharmacokinetic (PK) and clinical study data from 444 adult patients with ATL or CTCL collected during 6 clinical trials of mogamulizumab were used to construct a population PK model, which was best described by a 2-compartment model with linear clearance. Albumin, aspartate aminotransferase, mild-to-moderate hepatic impairment, and sex were statistically significant predictors of clearance; albumin was also a statistically significant predictor of peripheral volume of distribution; and body surface area was a statistically significant predictor for central volume of distribution. None of the other covariates-for example, age, body weight, body mass index, bilirubin, creatinine clearance, disease type (ATL and CTCL), ATL subtype (acute, lymphoma, and chronic), CTCL subtype (mycosis fungoides and Sézary syndrome), CCR4 expression (status or degree), race (Japanese and non-Japanese), renal impairment (normal, mild, moderate, and severe), or performance status-had a statistically significant impact. Performance of the final population PK model was acceptable. This model will be valuable for guiding further studies of mogamulizumab.

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty-eight patients were enrolled across the 3 drug-drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least-squares mean area under the plasma concentration-time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91-1.31) and was 1.11 (0.86-1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least-squares mean ratio of 0.26 [90%CI 0.18-0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least-squares mean ratio of 0.46 [90%CI 0.29-0.73]) in the presence of rifampin. The clinical drug-drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P-glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.

We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (C_ss ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models. Blinatumomab mean ± SD C_ss was 621 ± 502 pg/mL (28 μg/day dose). Cytokines were transiently elevated in >50% of patients; B-cell levels decreased in most patients. Lower B-cell and bone marrow (BM) blast percentages and higher T-cell percentages were associated with higher CR/CRh (P < .001) in univariate analysis. Higher C_ss (OR, 1.90; 95%CI, 1.12-3.21), higher peak IL-10 level (1.59; 1.13-2.22), and lower BM blast percentage (0.78; 0.69-0.89) were associated with higher CR/CRh in multivariate analysis. Higher C_ss (HR, 1.40; 1.01-1.94) and lower B-cell level (0.90; 0.84-0.97) were associated with shorter time to NEs. Cytokine peaks were not associated with NEs or CRS. In conclusion, blinatumomab led to T cell-mediated depletion of target B cells in blood and blasts in the bone marrow. Immune system effectiveness was important for treatment responses.

Myocardial injury following elective percutaneous coronary intervention (PCI) occurs in about one-third of patients and is associated with mortality. Platelet aggregation, thrombosis formation, and inflammation are the main causes of cardiac injury during PCI. Vitamin D plays a key role in the cardiovascular system by exerting antiplatelet, anticoagulant, and anti-inflammatory properties. There is no published study that investigated the effect of vitamin D in the prevention of cardiac injury following elective PCI. In a randomized clinical trial, 99 patients admitted for elective PCI were randomized into vitamin D (n = 52) and control (n = 47) groups. The intervention group received 300 000 IU vitamin D orally 12 hours before PCI. The cardiac biomarkers were checked at baseline, 8 and 24 hours after PCI. hs-CRP was also measured at baseline and after 24 hours. The increase in CK-MB was documented in 20 patients (42%) in the control group and 18 patients (34.6%) in the intervention group (P = .417). Furthermore, the increase in cTnI occurred in 4 patients (8%) and 2 patients (3.3%) in the control and intervention groups, respectively (P = .419). No significant changes were noted in the level of cardiac biomarkers. In the vitamin D group, the mean difference in CK-MB between 8 and 24 hours was significantly lower (P = .048). The mean difference in hs-CRP was significantly lower in the vitamin D group (P = .045). This study could not show a clear effect of vitamin D in the prevention of cardiac injury during elective PCI. Further outcome-based studies are needed to describe the role of vitamin D in the prevention of periprocedural myocardial injury.