Model-informed drug development of voxelotor in sickle cell disease: Population pharmacokinetics in whole blood and plasma.

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

Model-informed drug development of voxelotor in sickle cell disease: Exposure-response analysis to support dosing and confirm mechanism of action.

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents.

Pharmacokinetics and pharmacodynamics of a novel extended-release ciprofloxacin in healthy volunteers.

Two open-label, randomized, 2-way crossover studies (1 single-dose and 1 steady-state) were conducted in healthy volunteers to compare the pharmacokinetics and pharmacodynamics of a novel extended-release ciprofloxacin (ciprofloxacin ER; 500 mg once daily) and immediate-release ciprofloxacin (ciprofloxacin IR; 250 mg twice daily). For both studies, mean ciprofloxacin maximum concentration (Cmax) values after once-daily ciprofloxacin ER were significantly greater than those after the first daily dose of ciprofloxacin IR (P < .0001) but were lower than those after the second daily dose of ciprofloxacin IR (P < .05). The relative bioavailability of ciprofloxacin ER compared to ciprofloxacin IR was 93.8% in the single-dose study and 97.7% in the steady-state study. Mean urinary ciprofloxacin concentrations and excretion rates after either treatment were substantially greater than the minimum inhibitory concentrations (MICs) for susceptible uropathogens in both studies. The area under the concentration-time curve (AUC)/MIC, Cmax/MIC, amount excreted (Ae)/MIC, and Ae24/MIC ratios with ciprofloxacin ER were similar to or slightly greater than with ciprofloxacin IR for all susceptible organisms.

Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer.

PURPOSE: To characterize the population pharmacokinetics of trastuzumab in patients with metastatic breast cancer. METHODS: A nonlinear mixed effect model was based on pharmacokinetic data from phase I, II, and III studies of 476 patients. The phase I study enrolled patients with advanced solid tumors. The phase II and III studies enrolled patients with HER2-positive metastatic breast cancer. Patients in the pivotal phase II and III studies were treated with a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly for up to 840 days. The model adequately predicted observed trastuzumab concentrations. Model stability and performance were verified using bootstrap simulations. Percentiles, mean, and standard deviation of observed levels were compared with their distributions from 100 replicates of datasets simulated under the model. RESULTS: A two-compartment linear pharmacokinetic model best described the data and accounted for the long-term accumulation observed following weekly administration of trastuzumab. Population estimates from the base model for clearance (CL) and volume of distribution of the central compartment (V1) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated terminal halflife (t1/2) based on the population estimate was 28.5 days. Interpatient variabilities in clearance and volume were 43 and 29%, respectively. The number of metastatic sites, plasma level of extracellular domain of the HER2 receptor, and patient weight were significant baseline covariates for clearance, volume, or both (P<0.005). However, these covariate effects on trastuzumab exposure were modest and not clinically important in comparison with the large inter-patient variability of CL. Concomitant chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) did not appear to influence clearance. CONCLUSION: This population pharmacokinetic model can predict trastuzumab exposure in the long-term treatment of patients with metastatic breast cancer and provide comparison of alternative dosage regimens via simulation.

Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors.

OBJECTIVE: The aim of this study was to determine whether pharmacokinetic interactions between the protease inhibitors saquinavir soft gel, nelfinavir, and ritonavir are affected by the timing of administration. STUDY DESIGN: We used an open-label, 6-period, incomplete Latin square crossover study in 18 human immunodeficiency virus-negative subjects. Each received single oral doses of 2 of the 3 protease inhibitors during each of 6 periods. Single doses were given either simultaneously or separated by 4 hours. The order of the periods was balanced, and periods were separated by 2 days. We measured protease inhibitor concentrations over a 24-hour period by HPLC and estimated pharmacokinetic parameters by noncompartmental methods. RESULTS: Median saquinavir area under the curve (AUC) increased by 62-fold when ritonavir was coadministered, by 50-fold when ritonavir was given 4 hours earlier, and by 16-fold when saquinavir preceded ritonavir by 4 hours. Saquinavir AUC increased by 7-fold when nelfinavir was coadministered. Nelfinavir AUC increased by 2.5-fold with coadministration of ritonavir and by 1.8- and 2.1-fold when ritonavir was administered before nelfinavir and after nelfinavir, respectively. Ritonavir AUCs were unaffected by coadministration of the other drugs. The effect of ritonavir on the kinetics of saquinavir persisted for at least 48 hours after a single dose of ritonavir, suggesting the possibility of metabolic intermediates that form inhibitory complexes. CONCLUSION: Except for saquinavir followed by ritonavir, there is little difference in protease inhibitor exposure for simultaneous or staggered doses. The persistent effect of ritonavir suggests the possibility that lower doses and longer dosing intervals might be effective when ritonavir is used to boost concentrations of other protease inhibitors.