Ziad Hussein

Studies to Investigate the Pharmacokinetic Interactions Between Ranolazine and Ketoconazole, Diltiazem, or Simvastatin During Combined Administration in Healthy Subjects

The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open‐label and 4 double‐blind, randomized, multiple‐dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady‐state pharmacokinetics, safety, and tolerability of immediate‐ and sustained‐release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG‐CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4‐mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose‐dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and Cmax of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG‐CoA reductase activity by <2‐fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum

The population pharmacokinetics of atovaquone were examined in 458 black, Oriental, and Malay patients with acute Plasmodium falciparum malaria receiving atovaquone alone or concomitantly with other drugs. Oral clearance (CLF) showed a 0.674 power relationship with weight and is similar in Oriental and Malay subjects but 58.5% lower in black subjects. On the basis of mean body weight, the population estimate of CLF is 3.28, 8.49, and 9.13 L/hr in black, Oriental, and Malay subjects, respectively. The relationship between apparent volume of distribution (VareaF) and weight was linear and similar in all three races at 7.98 L/kg. The population estimate of VareaF is 345, 383, and 428 L in black, Oriental, and Malay subjects, respectively. The bioavailability of the high and low doses of atovaquone was similar. Neither CLF nor VareaF were significantly affected by age, gender, and thecoadministration with chloroguanide (proguanil), pyrimethamine, and tetracycline. Half‐life (t12) showed a 0.326 power relationship with weight; thus, the population estimate of t12 in black, Oriental, and Malay subjects is 72.9, 31.3, and 32.5 hours, respectively. The final magnitudes of interpatient variability in CLF and VareaF were 68% and 49%, respectively.

Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy

Objective: Evaluate the impact of concomitant enzyme (CYP3A4)-inducer antiepileptic drugs (EIAEDs) on the efficacy and safety of perampanel in patients from the 3 phase-III clinical trials. Methods: Patients with pharmacoresistant partial-onset seizures in the 3 phase-III clinical studies were aged 12 years and older and receiving 1 to 3 concomitant antiepileptic drugs. Following 6-week baseline, patients were randomized to once-daily, double-blind treatment with placebo or perampanel 8 or 12 mg (studies 304 and 305) or placebo or perampanel 2, 4, or 8 mg (study 306). Results: Treatment response assessed by median percent reduction in seizure frequency and responder rates improved with perampanel compared with placebo. However, at 8 and 12 mg, the treatment response was significantly greater in patients receiving non-EIAEDs. The treatment effect (perampanel–placebo) also demonstrated a dose-dependent increase in all patients. The overall incidence of treatment-emergent adverse events was similar regardless of the presence of EIAEDs. Occurrence of some adverse events, such as fatigue, somnolence, dizziness, irritability, was greater in patients receiving non-EIAEDs, as was discontinuation because of adverse events. Conclusions: Perampanel shows efficacy and safety in the presence and absence of EIAEDs. As systemic exposure to perampanel increases, so does efficacy. Given the extensive metabolism of perampanel, systemic exposure is clearly reduced with concomitant administration of CYP3A4 inducers. This supports the strategy of dosing perampanel to clinical effect. Recognition of these pharmacokinetic interactions will be important in the optimization of this novel medication. Classification of evidence: This study provides Class II evidence that 2 to 12 mg/d doses of perampanel reduced seizure frequency and improved responder rate in the presence and absence of EIAEDs.

Pharmacokinetics of Valproate After Multiple‐Dose Oral and Intravenous Infusion Administration: Gastrointestinal‐Related Diurnal Variation

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady‐state pharmacokinetics of valproate after multiple 250‐mg oral and intravenous infusion doses after an intravenous 750‐mg loading dose. Multiple blood samples were collected throughout each 168‐hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within‐regimen comparisons indicated statistically significant differences for mean steady‐state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration‐versus‐time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed‐release tablet preparation. Between‐regimen steady‐state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax (Tmax), Cmax, Cmin, AUC, and total body clearance for respective day‐4 dosing intervals, but not for the entire day 4, except for Cmin and Tmax. Mean elimination rate constant and half‐life did not significantly differ between the regimens. The regimens were bio‐equivalent at steady state, as assessed by 90% confidence intervals (two one‐sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation {(Cmax‐Cmin)/Caverage}. Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady‐state plasma concentration‐versus‐time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 μg/mL.

Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.

SummaryA double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers.Serial blood samples were collected for assessment of prothrombin times and R- and S- warfarin plasma concentrations.Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds.Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia.

AIMS Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. METHODS A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. RESULTS Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 10(9) neutrophils l(-1) [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l(-1) (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. CONCLUSIONS The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

AIMS Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. METHODS This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. RESULTS The final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h(-1) [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (-11.7%) and albumin (-6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (-7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. CONCLUSIONS The significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment.

Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2‐receptor antagonist AA‐2414 in normal subjects: Population analysis

The pharmacokinetics and pharmacodynamics of AA‐2414 [(±)‐7‐(3,5,6‐trimethyl‐l,4‐benzoquinon‐2‐yl)‐7‐phenylheptanoic acid] were evaluated in 39 healthy male subjects after four different oral multipledosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration–time profiles of AA‐2414 to be best characterized by a two‐compartment open model with zero‐order input and first‐order elimination. The final estimates for oral clearance, volume of distribution, and steady‐state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U‐46619, a thromboxane A2 mimetic, was significantly inhibited by AA‐2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 µmol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti‐platelet aggregation factor activity measurements were not significantly affected by administration of AA‐2414.

Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose‐independent, three‐compartment model with allometric relationship for body weight, was similar for all tumor types. Inter‐individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulins effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure–efficacy relationships to inform physicians treating patients with MBC.

Assessment of the pharmacokinetic interaction between zileuton and digoxin in humans.

SummaryThe effects of coadministration of zileuton on the pharmacokinetic profile of digoxin were investigated in a double-blind placebo-controlled crossover study in 12 healthy male volunteers. During each study phase, the subjects received zileuton 600mg every 6 hours (regimen A) or placebo (regimen B) for 13 days. In addition, all subjects received concomitant digoxin 0.25 mg/day on study days 1 to 11 during both study phases.The study results provide no evidence of any significant overall effect of zileuton on digoxin plasma concentration-time profiles. Although the mean time to reach the maximum plasma concentration for digoxin was significantly shorter after concomitant administration of digoxin and zileuton than after concomitant administration of digoxin and placebo (0.95 vs 1.43 hours), there were no significant differences between the 2 regimens in the values for maximum plasma concentration, area under the plasma concentration-time curve from 0 to 24 hours, elimination half-life, oral clearance, and apparent volume of distribution associated with the terminal phase.Therefore, it is concluded that digoxin and zileuton may be coadministered without risk of clinically relevant effects on the pharmacokinetic profile of digoxin.