Dataset Information

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

ABSTRACT: A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia versus allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (a single dose versus multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/liter) to a broad range of patients at high risk for invasive fungal disease.

SUBMITTER: van Iersel MLPS

PROVIDER: S-EPMC6021660 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

van Iersel Marlou L P S MLPS Rossenu Stefaan S de Greef Rik R Waskin Hetty H

Antimicrobial agents and chemotherapy 20180626 7

A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in hea ...[more]

PMID: 29712663

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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:IntroductionModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r.ObjectivesThis study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir.MethodsPatients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03.ResultsIn total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC)0-48, AUC0-inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93-1.33), 1.19 (90% CI 1.00-1.41) and 1.07 (90% CI 0.81-1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69-0.90), whereas the AUC0-48 and AUC0-inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity.ConclusionsThe docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS.Gov identifierNCT03147378, date of registration: May 10 2017.

Project description:To formulate hydroxypropyl methylcellulose-stabilized self-emulsifying solid dispersible carriers of noscapine to enhance oral bioavailability.Formulation of noscapine (Nos) self-emulsifying solid dispersible microparticles (SESDs) was afforded by emulsification using an optimized formula of Labrafil M1944, Tween-80, and Labrasol followed by spray-drying with hydroxypropyl methylcellulose (HPMC), with and without mannosamine (Mann-Nos_SESDs and Nos_SESDs respectively); self-microemulsifying liquid dispersions (SMEDDs) with and without mannosamine (Mann-Nos_SMEDDs and Nos_SMEDDs respectively) were also prepared. SMEDDs and SESDs were characterized for size, polydispersity, surface charge, entrapment efficiency, in vitro permeability, in vitro release kinetics, and oral pharmacokinetics in Sprague-Dawley rats (10 mg/kg p.o). The antitumor efficacy of Mann-Nos_SESDs on the basis of chemosensitization to cisplatin (2.0 mg/kg, i.v.) was investigated in a chemorefractory lung tumor Nu/Nu mouse model up to a maximal oral dose of 300 mg/kg.The oil/surfactant/co-surfactant mixture of Labrafil M1944, Tween-80, and Labrasol optimized at weight ratios of 62.8:9.30:27.90% produced stable self-microemulsifying dispersions (SMEDDs) at a SMEDD to water ratio of 1-3:7-9 parts by weight. SMEDDs had hydrodynamic diameters between 231 and 246 nm; surface charges ranged from -16.50 to -18.7 mV; and entrapment efficiencies were between 32 and 35%. SESDs ranged in size between 5.84 and 6.60 ?m with surface charges from -10.62 to -12.40 mV and entrapment efficiencies of 30.96±4.66 and 32.05±3.72% (Nos_SESDs and Mann-Nos_SESDs respectively). Mann-Nos_SESDs exhibited saturating uptake across Caco-2 monolayers (Papp = 4.94±0.18 × 10(-6) cm/s), with controlled release of 50% of Nos in 6 hr at pH 6.8 following Higuchi kinetics. Mann-Nos_ SESDs was 40% more bioavailable compared to Nos_SESDs; and was effective in sensitizing H1650 SP cells to Cisplatin in vitro and in an orthotopic lung tumor model of H1650 SP origin.Mannosylated noscapine self-emulsifying solid dispersions (Mann-Nos_SESDs) are bioavailable and potentiate the antineoplastic effect of cisplatin-based chemotherapy in cisplatin-resistant NSCLC.

Dataset Information

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

Publications

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

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