Journal of clinical pharmacology
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Randomized Controlled Trial Multicenter Study
Parent-Metabolite Pharmacokinetic Modeling and Pharmacodynamics of Veliparib (ABT-888), a PARP Inhibitor, in Patients With BRCA 1/2-Mutated Cancer or PARP-Sensitive Tumor Types.
Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single-agent veliparib in patients with either BRCA 1/2-mutated cancer or PARP-sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs). ⋯ Creatinine clearance(CLCR ) and lean body mass (LBM) were identified as significant predictors of veliparib CLR /F and central volume of distribution, respectively. For a typical subject (LBM, 48 kg; CLCR , 95 mL/min), total clearance (CLR /F + CLNR /F), and central and peripheral volume of distribution for veliparib were estimated as 17.3 L/h, 98.7 L, and 48.3 L, respectively. At least 50% inhibition of PAR levels in PBMCs was observed at dose levels ranging from 50 to 500 mg.
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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. ⋯ 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.
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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. ⋯ 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.