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Population pharmacokinetics of mycophenolic acid in renal transplant recipients.
Clin Pharmacokinet. 2005; 44(10):1083-96.CP

Abstract

BACKGROUND

Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics.

OBJECTIVE

The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters.

PATIENTS AND METHODS

Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling.

RESULTS

The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (k(a)) 4.1h(-1), central volume of distribution (V1) 91 L, peripheral volume of distribution (V2) 237 L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21 h. The interpatient variability for k(a), V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for k(a), V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001).

CONCLUSION

The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated.

Authors+Show Affiliations

Clinical Pharmacology Unit, Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands. r.vanhest@erasmusmc.nlNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16176120

Citation

van Hest, Reinier M., et al. "Population Pharmacokinetics of Mycophenolic Acid in Renal Transplant Recipients." Clinical Pharmacokinetics, vol. 44, no. 10, 2005, pp. 1083-96.
van Hest RM, van Gelder T, Vulto AG, et al. Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet. 2005;44(10):1083-96.
van Hest, R. M., van Gelder, T., Vulto, A. G., & Mathot, R. A. (2005). Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clinical Pharmacokinetics, 44(10), 1083-96.
van Hest RM, et al. Population Pharmacokinetics of Mycophenolic Acid in Renal Transplant Recipients. Clin Pharmacokinet. 2005;44(10):1083-96. PubMed PMID: 16176120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacokinetics of mycophenolic acid in renal transplant recipients. AU - van Hest,Reinier M, AU - van Gelder,Teun, AU - Vulto,Arnold G, AU - Mathot,Ron A A, PY - 2005/9/24/pubmed PY - 2006/1/13/medline PY - 2005/9/24/entrez SP - 1083 EP - 96 JF - Clinical pharmacokinetics JO - Clin Pharmacokinet VL - 44 IS - 10 N2 - BACKGROUND: Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics. OBJECTIVE: The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters. PATIENTS AND METHODS: Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling. RESULTS: The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (k(a)) 4.1h(-1), central volume of distribution (V1) 91 L, peripheral volume of distribution (V2) 237 L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21 h. The interpatient variability for k(a), V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for k(a), V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001). CONCLUSION: The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated. SN - 0312-5963 UR - https://www.unboundmedicine.com/medline/citation/16176120/Population_pharmacokinetics_of_mycophenolic_acid_in_renal_transplant_recipients_ L2 - https://dx.doi.org/10.2165/00003088-200544100-00006 DB - PRIME DP - Unbound Medicine ER -