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A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia.

ABSTRACT: The objective of this study was to support posaconazole dose regimens in pediatric patients aged ≥2 years, using a population pharmacokinetic (PK) approach with data from a phase 1b study (NCT02452034). A one-compartment model with first-order absorption was fit to pharmacokinetic data from 144 participants aged 2 to 17 years, who were administered posaconazole as intravenous (IV) and powder for oral suspension (PFS) formulations, or IV only, at dosing regimens of 3.5, 4.5, and 6 mg/kg. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final model simulated posaconazole exposure in patients aged 2 to <7 and 7 to 17 years at dosing regimens of 4.5, 6, and 7.5 mg/kg. Plasma concentration data following IV and PFS administration were well-described by a one-compartment model with first-order absorption and estimated bioavailability, where clearance and volume were subject to allometric scaling by body weight. The 6-mg/kg dosing regimen achieved the pharmacokinetic target (90% of the pediatric population having an average steady-state plasma concentration of ≥500 and <2,000 ng/mL) for both age groups, regardless of whether patients received IV and PFS or IV only. In a virtual adolescent population (body weight >40 kg), the 300 mg/day posaconazole tablet was also predicted to achieve the pharmacokinetic target and remain within a safe range of exposure. These data informed a weight-based nomogram for PFS dosing to maximize the number of pediatric patients achieving the pharmacokinetic target across weight bands, while also maintaining a favorable benefit/risk profile.

SUBMITTER: Winchell G

PROVIDER: S-EPMC10994819 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia.

Winchell Gregory G de Greef Rik R Ouerdani Aziz A Fauchet Floris F Wrishko Rebecca E RE Mangin Eric E Bruno Christopher C Waskin Hetty H

Antimicrobial agents and chemotherapy 20240220 4

The objective of this study was to support posaconazole dose regimens in pediatric patients aged ≥2 years, using a population pharmacokinetic (PK) approach with data from a phase 1b study (NCT02452034). A one-compartment model with first-order absorption was fit to pharmacokinetic data from 144 participants aged 2 to 17 years, who were administered posaconazole as intravenous (IV) and powder for oral suspension (PFS) formulations, or IV only, at dosing regimens of 3.5, 4.5, and 6 mg/kg. The infl ...[more]

PMID: 38376229

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Project description:Abstract Background Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean Cavg and individual Cavg ≥500 ng/mL and <2500 ng/mL in ~90% of patients. Methods A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2–<7 years and 7–17 years). Posaconazole IV was administered twice on day 1 then once daily through at least day 10, followed by PFS once daily through day 28 at clinician discretion. A compartmental model, including both formulations, was fit to the data. Model selection was based on the Log-Likelihood Criterion, goodness-of-fit plots, and scientific plausibility. Significance of the covariates was assessed in a stepwise forward inclusion/backward procedure. An additional assessment characterized the impact of different food covariates on bioavailability. Results An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted Cavg generally met PK targets. Model-predicted Cavg was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean Cavg was achieved for all but the 2–<7 years cohort receiving the PFS formulation. Conclusion This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food. Disclosures All authors: No reported disclosures.

Project description:BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS:The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION:The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01716234.

Project description:To evaluate the safety, tolerability, and comparative pharmacokinetics (PK) of intravenous and oral carbamazepine.In this phase 1, open-label study, adult patients with epilepsy on a stable oral carbamazepine dosage (400-2,000 mg/day) were converted to intravenous carbamazepine (administered at 70% of the oral dosage). A 28-day outpatient period preceded an up to 10-day inpatient period and a 30-day follow-up period. Intravenous carbamazepine was administered over 15 or 30 min every 6 h on days 1-7; some patients in the 15-min group were eligible to receive four 2- to 5-min (rapid) infusions on day 8. Patients underwent blood sampling to determine the area under the concentration-time curve (AUC) for carbamazepine and metabolite carbamazepine-10,11-epoxide following oral (day 0) and intravenous carbamazepine administration (days 1, 7, and 8). Bioequivalence was evaluated in patients with normal renal function (creatinine clearance >80 ml/min). Safety assessments were conducted through day 38.Ninety-eight patients enrolled and 77 completed the PK component. The mean daily oral and intravenous carbamazepine dosage for 64 PK-evaluable patients with normal renal function was 962.5 and 675.1 mg (70% of oral dosage), respectively. Steady-state minimum concentration (C(min)) and overall exposure (AUC0-24) for intravenous carbamazepine infused over 30, 15, or 2-5 min were similar to oral carbamazepine. The 90% confidence intervals (CIs) for the ratios of the adjusted means for AUC0-24, maximum concentration (Cmax), and C(min) were within the 80%-125% bioequivalence range for 30-min intravenous infusions versus oral administration, but exceeded the upper limit for Cmax for the 15-min and rapid infusions. All intravenous carbamazepine infusions were well tolerated.Intravenous carbamazepine infusions (70% of oral daily dose) of 30-, 15-, and 2- to 5-min duration, given every 6 h, maintained patients' plasma carbamazepine concentrations. Intravenous carbamazepine 30-min infusions were bioequivalent to oral carbamazepine in patients with normal renal function; rapid infusions were well-tolerated in this study.

Project description:Posaconazole is more active than fluconazole against Candida albicansin vitro and is approved for the treatment of oropharyngeal candidiasis but not for that of invasive candidiasis (IC). Here, we explored the efficacy of posaconazole against C. albicans in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model of IC and determined the probability of pharmacodynamic target attainment for the oral solution and intravenous (i.v.)/tablet formulations. Three clinical C. albicans isolates (posaconazole MICs, 0.008 to 0.25 mg/liter) were studied in the in vitro PK/PD dilution model simulating steady-state posaconazole PK. The in vitro exposure-effect relationship, area under the 24-h free drug concentration curve (fAUC0-24)/MIC, was described and compared with in vivo outcome in animals with IC. PK/PD susceptibility breakpoints and trough levels required for optimal treatment were determined for EUCAST and CLSI 24-h/48-h (CLSI24h/CLSI48h) methods using the fAUC0-24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis for oral solution (400 mg every 12 hours [q12h]) and i.v./tablet formulations (300 mg q24h). The in vitro mean (95% confidence interval [CI]) EI50 was 330 (183 to 597) fAUC0-24/MIC for CLSI24h and 169 (92 to 310) for EUCAST/CLSI48h methods, which are close to the near-stasis in vivo effect. The probability of target attainment for EI50 was estimated; for the wild-type isolates (MIC ≤ 0.06 mg/liter), it was low for the oral solution and higher than 95% for the i.v./tablet formulations for the EUCAST/CLSI48h methods but not for the CLSI 24-h method. Non-wild-type isolates with EUCAST/CLSI48h MICs of 0.125 and 0.25 mg/liter would require trough levels of >1.2 and >2.4 mg/liter, respectively. Posaconazole i.v./tablet formulations may have a role in the therapy of invasive infections by wild-type C. albicans isolates, provided that a steady state is reached quickly. A PK/PD susceptibility breakpoint at the epidemiological cutoff (ECV/ECOFF) of 0.06 mg/liter was determined.

Dataset Information

A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia.

Publications

A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia.

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