Dataset Information

Population pharmacokinetics of deferiprone in healthy subjects.

ABSTRACT:

Aims

To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure.

Methods

Data from 55 adult healthy subjects receiving deferiprone (solution 100?mg?ml(-1)) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries.

Results

A one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4?mg?l(-1) ?h, whereas Cmax increased from 17.6 to 26.5?mg?l(-1) after administration of 25 and 75?mg?kg(-1) doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CLcr . Doses of 60, 40 and 25?mg?kg(-1) for patients showing mild, moderate and severe renal impairment are proposed based on CLcr values of 60-89, 30-59 and 15-29?ml?min(-1), respectively.

Conclusions

Our analysis has enabled the assessment of the impact of gender and CLcr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone.

SUBMITTER: Bellanti F

PROVIDER: S-EPMC4256628 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

Population pharmacokinetics of deferiprone in healthy subjects.

Bellanti Francesco F Danhof Meindert M Della Pasqua Oscar O

British journal of clinical pharmacology 20141201 6

<h4>Aims</h4>To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure.<h4>Methods</h4>Data from 55 adult healthy subjects receiving deferiprone (solution 100 mg ml(-1)) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition w ...[more]

PMID: 25052529

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Project description:BACKGROUND AND OBJECTIVES:Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure. METHODS:Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations. RESULTS:A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight. CONCLUSIONS:Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure. TRIAL REGISTRATION:ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.

Dataset Information

Population pharmacokinetics of deferiprone in healthy subjects.

Aims

Methods

Results

Conclusions

Publications

Population pharmacokinetics of deferiprone in healthy subjects.

Similar Datasets

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