Characterization of the Time Course of Carbamazepine Deinduction by an Enzyme Turnover Model

Punyawudho, Baralee; Cloyd, James C.; Leppik, Ilo E.; Ramsay, R. Eugene; Marino, Susan E.; Pennell, Page B.; White, James R.

doi:10.2165/00003088-200948050-00003

Cited by 27 publications

(19 citation statements)

References 25 publications

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“…The estimates of V/F and K a were 102 L (IIV = 74%) and 0.197 hr −1 , respectively. Based on the parameter estimates from the final model, carbamazepine half-life was approximately 19.7 hours in this community dwelling elderly patients which was consistent with the values estimated from adult patients of 10–20 hours [19, 20]. These values may provide a more population specific estimate of maintenance and loading doses in the community-dwelling elderly population.…”

Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Punyawudho

Ramsay²,

Brundage³

et al. 2012

Therapeutic Drug Monitoring

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Background Carbamazepine is a commonly used antiepileptic drug in elderly patients. This study analyzed prospective data collected as part of a randomized, double-blinded trial of newly diagnosed epilepsy patients. The aims of this study were to determine the pharmacokinetic parameters and their variability of carbamazepine in elderly patients and to quantify the effect of covariates on these parameters. Methods Prospectively collected carbamazepine concentrations from 121 patients aged 60 years or older were used to develop a population pharmacokinetic model. Data were analyzed by a nonlinear mixed effects model (NONMEM). A one-compartment model with first order absorption and elimination was used to characterize the time course of carbamazepine concentration. Model evaluation and the predictive performance of the final model were assessed using the nonparametric bootstrap approach. Results The apparent clearance (CL/F) of carbamazepine in this community-dwelling elderly population was estimated to be 3.59 L/hr with an inter-individual variability of 18.1%. The CL/F increases 23% in patients co-medicated with phenytoin. The volume of distribution (V/F) was estimated to be 102 L with an inter-individual variability of 74.7%. Conclusions Carbamazepine clearance was not associated with body weight or any parameterization of body size, nor was age or race, nor any marker of hepatic or renal function. Patients on concurrent phenytoin therapy can be expected to require a 23% higher dose on average.

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Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Punyawudho

Ramsay²,

Brundage³

et al. 2012

Therapeutic Drug Monitoring

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“…59 Consequently, individualization of the doses or better the therapeutic plasma concentrations of antipsychotics, such as RIS, using TDM should be considered to maintain a favorable antipsychotic effect when CBZ is coadministered, or to avoid adverse reactions when a CYP-inducing comedication is stopped. 60,61 Especially in the case of CBZ discontinuation, Punyawudho and colleagues 62 estimated that enzyme induction should be reduced by about half after 3 days of discontinuation, by 75% after 7 days and a return to a normal status might be achieved after 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

Schoretsanitis¹,

Haen²,

Gründer³

et al. 2016

J Clin Psychopharmacol

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Background: The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions.Methods: A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R 0 , n = 852), a group comedicated with valproate (VPA) (R VPA , n = 153), a group comedicated with lamotrigine (LMT) (R LMT , n = 46), and a group under concomitant medication with carbamazepine (CBZ) (R CBZ , n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS) were computed.Results: Groups did not differ with regard to the daily dosage (P = 0.46).Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM (P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction (P = 0.0125). Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group (P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS (P < 0.001) as well as the AM (P < 0.001) than the control group; this difference survived the Bonferroni correction. Conclusions:The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.Key Words: therapeutic drug monitoring, risperidone, carbamazepine, valproic acid, lamotrigine cytochrome P450, interaction, pharmacokinetics (J Clin Psychopharmacol 2016;36: 00-00) G uidelines worldwide recommend the coadministration of second-generation antipsychotics as augmentative therapy to mood stabilizers or vice versa in the treatment of bipolar disorders, especially for the treatment of manic episodes.1-3 Acceptance of this strategy which promises better efficacy 4 despite a higher potential of adverse events 5,6 is reflected in increasing prescription trends. 7 Many pharmacokinetic drug-drug interactions (DDIs) have been identified by therapeutic drug monitoring (TDM) as TDM databases enable evaluation of pharmacokinetic DDIs in a representative population to get an insight into the safety and tolerability of combined psychopharmacological ...

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“…To reduce the risk of organ rejection, adjustment (increase) of immunosuppressant doses is required with continuous monitoring of immunosuppressant blood levels. Furthermore, the CYP3A4 deinduction process can last for about 2 weeks after cessation of carbamazepine or valproic acid [137]; thus, careful monitoring of immunosuppressant blood concentrations during withdrawal is essential. The comedication with the antidepressant fluvoxamine is contraindicated because of its strong inhibitory properties for CYP3A4 substrates and potential drug interactions with ciclosporin/tacrolimus or with sirolimus/everolimus [80,138,139].…”

Section: Psychiatric Medicationmentioning

confidence: 99%

Metabolic Drug Interactions with Immunosuppressants

Monostory¹

2018

Organ Donation and Transplantation - Current Status and Future Challenges

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Organ transplantation has become a routine clinical practice for patients with endstage disease of liver, kidney, heart, or lung. Although improved immunosuppressant therapy substantially contributes to the success of transplantation, clinicians continue to face challenges because of wide interindividual variations in blood concentrations resulting in subtherapeutic or supratherapeutic levels. Many undesired side-effects or therapeutic failure of immunosuppressants as a consequence are the results of differences or changes in drug metabolism. Considering genetic and nongenetic factors, such as co-medication, can refine the immunosuppressant therapy, facilitating personalized treatments to individual recipients. This review provides an up-to-date summary of functional polymorphisms of enzymes involved in the metabolism of immunosuppressants with low molecular weight and of the clinical significance of metabolic drug interactions between immunosuppressive agents and other drugs in therapeutic regimens of transplant recipients.

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Characterization of the Time Course of Carbamazepine Deinduction by an Enzyme Turnover Model

Cited by 27 publications

References 25 publications

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

Metabolic Drug Interactions with Immunosuppressants

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