Journal of clinical pharmacology最新文献

Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects. Natalizumab PK was best described using a 2-compartment model with linear first-order and Michaelis-Menten elimination. Subcutaneous absorption of natalizumab was characterized using first-order absorption with lag time. The relationship between natalizumab concentration and alpha-4 integrin saturation (PD) was best described by a direct response model with a sigmoidal effect on alpha-4 integrin saturation mediated by a maximum effect relationship with natalizumab concentrations. Covariate analysis showed that body weight, product formulations, and the presence of antinatalizumab antibodies were the main covariates affecting natalizumab PK, whereas age and formulations affected PD. The use of simulations based on a pharmacokinetic-pharmacodynamic model showed that covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen of natalizumab (300 mg once every 4 weeks).

Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose-HR-QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations. The final model includes stimulatory drug effects on glucose elimination and HR perturbations. The targeted and constant exenatide plasma concentrations (>200 pg/mL), via intravenous infusions at multiple dose levels, resulted in significant inhibition of glucose concentrations. The exenatide concentration associated with 50% of the stimulation of HR production was 584 pg/mL. After accounting for exenatide effects on glucose and HR, no additional drug effects were required to explain observed changes in the QT interval. Resulting glucose, HR, and QT profiles at all exenatide concentrations were adequately described. For therapeutic agents that alter glycemic conditions, particularly those that alter postprandial glucose, the QT interval cannot be directly compared to that with placebo without first accounting for confounding factors (eg, glucose) either through mathematical modeling or careful consideration of mealtime placement in the study design.

Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Q_p = 0.572 L/h, Q_CSF = 0.069 L/h, CL_p = 2.50 L/h, CL_CSF = 0.133 L/hr, V_CSF = 0.441 L, V_p = 32.0 L, V_{systemic_tissue} = 429 L, and V_{CNS_tissue} = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on V_CSF , V_p , and CL_p . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.

Roflumilast is a selective phosphodiesterase 4 inhibitor (PDE4i) for the treatment of severe chronic obstructive pulmonary disease (COPD). In 2 large phase 3 trials in a broader population of COPD patients (BY217/M2-111, ClinicalTrials.gov: NCT00076089 and BY217/M2-112, ClinicalTrials.gov: NCT00430729), treatment with roflumilast reduced the rate of exacerbations; however, the reduction did not reach statistical significance. Two linked dose-response models for the primary (annualized COPD exacerbation counts) and secondary (change from baseline in forced expiratory volume in 1 second [FEV₁ ]) end points were therefore developed to characterize and quantify effect sizes and the patient characteristics influencing them. The models showed that disease severity and bronchitis, particularly the severity of bronchitis expressed in cough-and-sputum scores, were good predictors of exacerbation rates and differential benefit of roflumilast in exacerbation reduction. The models were used to support the rational design of 2 phase 3 randomized, placebo-controlled clinical trials (BY217/M2-124, ClinicalTrials.gov: NCT00297102 and BY217/M2-125, ClinicalTrials.gov: NCT00297115) by identifying the most appropriate patient population using clinical trial simulations. Model predictions for both end points were found to be highly accurate - as confirmed by the results from these trials, which led to the approval of roflumilast as the first oral PDE4i for the treatment of COPD in patients associated with chronic bronchitis and a history of exacerbations.

To date, the relationship between antimuscarinics for overactive bladder (OAB) syndrome and depressive disorder still remains unclear. Therefore, this retrospective cohort study examined the association between antimuscarinic use and the subsequent risk of depressive disorder using a population-based data set. This study used data from the Taiwan Longitudinal Health Insurance Database 2005. We selected 1952 OAB women who received antimuscarinics as the study cohort and 9760 OAB women who did not receive antimuscarinics as the comparison cohort. Each subject was tracked for 3 years from her index date to determine all those who were subsequently diagnosed with depressive disorder. Results indicated that the adjusted hazard ratio (HR) for depressive disorder in OAB women who received antimuscarinics was 1.38 (95% confidence interval [CI], 1.15-1.64) compared with those OAB women who did not receive antimuscarinics. In addition, the adjusted HRs for subsequent depressive disorder for OAB women aged 18-39, 40-59, and ≥60 years who received antimuscarinics were 1.83 (95%CI, 1.27-2.64), 1.36 (95%CI, 1.03-1.81), and 1.16 (95%CI, 0.86-1.56), respectively, compared with those OAB women who did not receive antimuscarinics. We concluded that women with OAB who received antimuscarinics had a significantly higher risk of subsequent depressive disorder compared with those OAB women who did not receive antimuscarinics. Accordingly, clinicians should be alert to the relationship between antimuscarinics usage and depressive disorder in OAB women and provide appropriate instructions for these patients.

The sphingosine-1-phosphate 1 receptor (S1P_1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P_1R and S1P_5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation.

Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low-density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W. Data were digitized from published studies describing alirocumab and evolocumab PK, as well as LDLc levels in humans for various single and multiple doses. Alirocumab dosages ranged between 75 and 300 mg and evolocumab from 7 to 420 mg. The analysis was performed using a nonlinear mixed-effects modeling technique. A 2-compartment model with first-order absorption and saturable elimination described the PK of both antibodies best. LDLc levels were described by a turnover model with zero-order synthesis rate decreased by the antibodies and a first-order degradation rate that was increased by the antibodies. Simulations show a comparable effectiveness for alirocumab 75 mg Q2W and 150 mg Q3W as well as evolucmab 140 mg Q2W and 420 mg Q5W, respectively. This is the first PK/PD model describing the link between alirocumab and evolocumab PK and LDLc concentrations. The model may serve as an important tool to simulate different dosage regimens in order to optimize therapy.

Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150-kDa human IgG1 antibody interacting with a soluble target.