Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory Emax function of Cmin on the seizure mean, where Emax exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.

Modeling and Simulation Support Eltrombopag Dosing in Pediatric Patients With Immune Thrombocytopenia.

Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in two clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including three pharmacokinetic and four pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules. This work supported initial eltrombopag doses of 50 mg once daily (q.d.) for non-Asian patients aged ≥ 6 years and 25 mg q.d. for Asian patients, regardless of age, and for all patients aged 1-5 years, regardless of ethnic origin. Doses were escalated at 2-week intervals or reduced as needed according to each patient's platelet counts to both minimize the time to achieve target platelet counts and mitigate thrombocytosis. Clinicaltrials.gov Identifier: NCT00908037, NCT01520909.

Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia.

PURPOSE: We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML). METHODS: Concentration data from 493 patients with CML in chronic phase (CML-CP), accelerated phase, or blast crisis were used to perform a population pharmacokinetic analysis using nonlinear mixed-effect modeling. Steady-state nilotinib trough concentrations (Cmin) in individual patients were estimated from the population PK model for correlation with the efficacy and safety variables. Exposure-efficacy analysis was performed in patients with CML-CP, whereas exposure-safety analysis was performed in all patients who had both nilotinib PK data and efficacy/safety measures available. RESULTS: Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower Cmin had significantly longer time to complete cytogenetic response (P = 0.010), longer time to major molecular response (P = 0.012), shorter time to progression (TTP; P = 0.009), and a trend toward lower response rates vs. patients with higher Cmin. A joint effect of prognostic risk score and Cmin on TTP was significant (P < 0.001). Nilotinib Cmin was also associated with the occurrence of all-grade elevations in total bilirubin (P < 0.001) and lipase (P = 0.002) levels. CONCLUSIONS: When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient Cmin is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.

Single-dose pharmacokinetics of famciclovir in infants and population pharmacokinetic analysis in infants and children.

A multicenter, open-label study evaluated the single-dose pharmacokinetics and safety of a pediatric oral famciclovir (prodrug of penciclovir) formulation in infants aged 1 to 12 months with suspicion or evidence of herpes simplex virus infection. Individualized single doses of famciclovir based on the infant's body weight ranged from 25 to 175 mg. Eighteen infants were enrolled (1 to <3 months old [n = 8], 3 to <6 months old [n = 5], and 6 to 12 months old [n = 5]). Seventeen infants were included in the pharmacokinetic analysis; one infant experienced immediate emesis and was excluded. Mean C(max) and AUC(0-6) values of penciclovir in infants <6 months of age were approximately 3- to 4-fold lower than those in the 6- to 12-month age group. Specifically, mean AUC(0-6) was 2.2 microg h/ml in infants aged 1 to <3 months, 3.2 microg h/ml in infants aged 3 to <6 months, and 8.8 microg h/ml in infants aged 6 to 12 months. These data suggested that the dose administered to infants <6 months was less than optimal. Eight (44.4%) infants experienced at least one adverse event with gastrointestinal events reported most commonly. An updated pharmacokinetic analysis was conducted, which incorporated the data in infants from the present study and previously published data on children 1 to 12 years of age. An eight-step dosing regimen was derived that targeted exposure in infants and children 6 months to 12 years of age to match the penciclovir AUC seen in adults after a 500-mg dose of famciclovir.

The effect of food consumption on lumefantrine bioavailability in African children receiving artemether-lumefantrine crushed or dispersible tablets (Coartem) for acute uncomplicated Plasmodium falciparum malaria.

OBJECTIVES: Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria. METHODS: In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed. RESULTS: The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29-96%) with crushed tablets and 65% (90% CI: 28-109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0-99.7%)] and was not related to food intake. CONCLUSIONS: AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.

Population pharmacokinetics of valsartan in pediatrics.

The objective of this work was to develop a population pharmacokinetic model to assess the influence of subject covariates on the pharmacokinetics of valsartan in children. Data were collected from a single dose study in 26 hypertensive children ages 1 to 16 years. Subjects received 2 mg/kg valsartan suspension up to a maximum dose of 80 mg. Plasma samples were collected and analyzed using LC/MS/MS. Several structural pharmacokinetic models were evaluated for appropriateness. Allometric scaling and standard covariate analyses were performed to explain interindividual variabilities. Objective function values and goodness of fit plots were used for model selection. A posterior predictive check was used for model evaluation. A linear 2-compartment first-order elimination model with zero-order absorption and lag-time best described the disposition of valsartan. Allometric scaling and standard covariate analysis revealed that age and body size have similar influence; however, after adjustment for body size using fat free mass (FFM), the effect of increasing age was no longer significant on valsartan clearance (2% per year relative to a typical 8 year old with FFM of 30 kg). The population pharmacokinetic model reveals that increase in age has minimal influence on body size dependent clearance of valsartan in children.

Population pharmacokinetics of telbivudine and determination of dose adjustment for patients with renal impairment.

Telbivudine is a new nucleoside analog indicated for the treatment of chronic hepatitis B infection. A population pharmacokinetic model was developed based on data pooled from 16 early phase studies in 363 healthy participants and patients. Telbivudine was administered as single and/or multiple doses of 25 to 1800 mg daily for up to 28 days. A 2-compartment model with first-order input and lag time provided the best fit to the data. A final model was built with identified covariates, including creatinine clearance on plasma clearance, dose and race on bioavailability fraction, and body weight on central volume of distribution. The final model was applied to simulate steady-state exposure for patients with impaired renal function for various dosing regimens. Results from these simulation analyses support that in patients with moderate to severe renal impairment or end-stage renal disease, reduced daily doses of telbivudine could be an alternative to interval adjustment to achieve exposure comparable to patients with normal renal function or mild renal impairment treated with the full clinical dose.

A mechanism-based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab.

AIM: Omalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations. METHODS: An instantaneous equilibrium drug-ligand binding and turnover population model was built from 202 Japanese patients. A posterior predictive evaluation for the steady-state distributions of omalizumab and IgE was then carried out against 531 White patients. RESULTS: The mean parameters estimated from the Japanese patients were as follows: omalizumab clearance 7.32 +/- 0.153 ml h(-1), IgE clearance 71.0 +/- 4.68 ml h(-1) and the difference between that for omalizumab and the complex 5.86 +/- 0.920 ml h(-1), the volume of distribution for omalizumab and IgE 5900 +/- 107 ml, and that for the complex 3630 +/- 223 ml, the rate of IgE production 30.3 +/- 2.04 microg h(-1). Half-lives of IgG (23 days) and IgE (2.4 days) were close to previous reports. The dissociation constant for binding, 1.07 nM, was similar to in vitro values. Clearance and volume of distribution for omalizumab varied with bodyweight, whereas the clearance and rate of production of IgE were predicted accurately by baseline IgE. Overall, these covariates explained much of the interindividual variability. CONCLUSIONS: The predictiveness of the Japanese model was confirmed by Monte-Carlo simulations for a White population, also providing evidence that the pharmacokinetics of omalizumab and IgE were similar in these two populations. Furthermore, the model enabled the estimation of not only omalizumab disposition parameters, but also the binding with and the rate of production, distribution and elimination of its target, IgE.

Pharmacokinetic drug interactions in children taking oxcarbazepine.

OBJECTIVE: Our objective was to evaluate the drug-drug interactions of oxcarbazepine with coadministered antiepileptic drugs in children. METHODS: In a clinical trial, pediatric patients receiving an oxcarbazepine dose titrated to 30 to 46 mg. kg(-1). d(-1) given twice daily had 1 to 4 blood samples collected per patient for population pharmacokinetic analysis of oxcarbazepine's major bioactive 10-monohydroxy metabolite. With the use of NONMEM, 7 concomitant antiepileptic drugs and 12 additional covariates were examined for their effects on the pharmacokinetics of 10-monohydroxy metabolite. In addition, for each concomitant antiepileptic drug, the ratio of its mean concentration with coadministration of oxcarbazepine to that without coadministration at baseline was calculated to evaluate the effect of oxcarbazepine on the coadministered antiepileptic drugs. RESULTS: The population pharmacokinetic data for 10-monohydroxy metabolite consisted of a total of 376 observations from 109 patients, aged 3 to 17 years. Body surface area and 3 antiepileptic drugs (carbamazepine, phenobarbital, and phenytoin) were significant predictors of the apparent clearance of 10-monohydroxy metabolite, whereas height was a significant predictor of apparent volume. Weight-normalized clearance of 10-monohydroxy metabolite was higher in young children than in older children and adults. Carbamazepine, phenobarbital, or phenytoin administered with oxcarbazepine increased the apparent clearance of 10-monohydroxy metabolite by 31% to 35%, whereas carbamazepine levels decreased by 15% and phenobarbital levels increased by 14%. CONCLUSIONS: Oxcarbazepine has a low propensity to inhibit or induce oxidative enzymes. Young children could be given higher milligrams-per-kilogram oxcarbazepine doses than older children and adults to achieve the same mean steady-state concentration of 10-monohydroxy metabolite. The adjustment is based simply on body size.