Implementation of dose superimposition to introduce multiple doses for a mathematical absorption model (transit compartment model)

Shen, Jun; Boeckmann, Alison; Vick, Andrew

doi:10.1007/s10928-012-9247-3

Cited by 24 publications

(25 citation statements)

References 10 publications

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“…Because a previous dose may not be absorbed completely before the next dosing time, we used the NONMEM code provided by Shen et al14 to implement the dose superimposition. We also sought to implement Weibull-type absorption for dose superimposition, but failed to estimate appropriate parameters.…”

Section: Discussionmentioning

confidence: 99%

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model

Hong

Han

Jeon³

2016

DDDT

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Pregabalin is an anticonvulsant used for the treatment of neuropathic pain and partial seizure in adults. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the absorption characteristics of pregabalin given fasted or after meals. Data from five healthy subject PK studies (n=88) of single- or multiple-dose pregabalin (150 mg) were used. Pregabalin was administered twice daily, without meals or 30 min after a meal (regular or high-fat diet) in the morning and 30 min or 4 h after a meal (regular diet) in the evening. Serial plasma samples were collected up to 24 h after the last dose for PK analysis. Because the peak concentrations were not properly modeled by a conventional first-order absorption model, Erlang frequency distribution, Weibull-type absorption, and transit compartment models were tested on a two-compartment linear PK model using a nonlinear mixed-effects method (NONMEM; version 7.3). The transit compartment model best described the absorption characteristics of pregabalin regardless of meal status. We conclude that the absorption model should be carefully chosen based on the principle of model development and validation and not by following a conventional first-order absorption model for its popularity and simplicity, especially when the PK dataset includes densely sampled absorption-phase data.

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Section: Discussionmentioning

confidence: 99%

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model

Hong

Han

Jeon³

2016

DDDT

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“…The gradual onset of oral drug absorption was described with a chain of transition compartments, as described earlier (49). In short, the mean absorption time (MAT) was estimated and the rate constant ( k tr ) for these transition compartments was calculated using the equation k tr = ( n + 1)/MAT, where n equals the number of transition compartments.…”

Section: Methodsmentioning

confidence: 99%

Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children

Gonçalves

Pett

Tiono

et al. 2017

Antimicrob Agents Chemother

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Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine. (This study has been registered at ClinicalTrials.gov under registration no. NCT01935882.)

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“…Due to the erratic and incomplete absorption associated with the posaconazole suspension (5, 9), a range of approaches were investigated to describe posaconazole absorption. These included first-order absorption (with and without absorption lag time), dose-dependent saturable absorption, and a multipledose transit compartment model (22). Interindividual variability (IIV) and interoccasion variability (IOV; also termed intraindividual variability) in posaconazole pharmacokinetic parameters were evaluated by using exponential error models.…”

Section: Methodsmentioning

confidence: 99%

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

Dolton

Brüggemann

Burger

et al. 2014

Antimicrob Agents Chemother

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c Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drugdrug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.

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Implementation of dose superimposition to introduce multiple doses for a mathematical absorption model (transit compartment model)

Cited by 24 publications

References 10 publications

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model

Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

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