Importance of hematocrit for a tacrolimus target concentration strategy
- Elisabet StørsetAffiliated withDepartment of Transplant Medicine, Oslo University Hospital, RikshospitaletInstitute of Clinical Medicine, University of Oslo Email author
- , Nick HolfordAffiliated withDepartment of Pharmacology and Clinical Pharmacology, University of Auckland
- , Karsten MidtvedtAffiliated withDepartment of Transplant Medicine, Oslo University Hospital, Rikshospitalet
- , Sara BremerAffiliated withDepartment of Medical Biochemistry, Oslo University Hospital, Rikshospitalet
- , Stein BerganAffiliated withDepartment of Pharmacology, Oslo University Hospital, Rikshospitalet
- , Anders ÅsbergAffiliated withDepartment of Transplant Medicine, Oslo University Hospital, RikshospitaletSchool of Pharmacy, University of Oslo
To identify patient characteristics that influence tacrolimus individual dose requirement in kidney transplant recipients.
Data on forty-four 12-h pharmacokinetic profiles from 29 patients and trough concentrations in 44 patients measured during the first 70 days after transplantation (1,546 tacrolimus whole blood concentrations) were analyzed. Population pharmacokinetic modeling was performed using NONMEM 7.2®.
Standardization of tacrolimus whole blood concentrations to a hematocrit value of 45 % improved the model fit significantly (p < 0.001). Fat-free mass was the best body size metric to predict tacrolimus clearance and volume of distribution. Bioavailability was 49 % lower in expressers of cytochrome P450 3A5 (CYP3A5) than in CYP3A5 nonexpressers. Younger females (<40 years) showed a 35 % lower bioavailability than younger males. Bioavailability increased with age for both males and females towards a common value at age >55 years that was 47 % higher than the male value at age <40 years. Bioavailability was highest immediately after transplantation, decreasing steeply thereafter to reach its nadir at day 5, following which it increased during the next 55 days towards an asymptotic value that was 28 % higher than that on day 5.
Hematocrit predicts variability in tacrolimus whole blood concentrations but is not expected to influence unbound (therapeutically active) concentrations. Fat-free mass, CYP3A5 genotype, sex, age and time after transplant influence the tacrolimus individual dose requirement. Because hematocrit is highly variable in kidney transplant patients and increases substantially after kidney transplantation, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations.
KeywordsTacrolimus Hematocrit Fat-free mass Population pharmacokinetics Target concentration intervention Kidney transplantation
- Importance of hematocrit for a tacrolimus target concentration strategy
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- Available under Open Access This content is freely available online to anyone, anywhere at any time.
European Journal of Clinical Pharmacology
Volume 70, Issue 1 , pp 65-77
- Cover Date
- Print ISSN
- Online ISSN
- Springer Berlin Heidelberg
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- Fat-free mass
- Population pharmacokinetics
- Target concentration intervention
- Kidney transplantation
- Industry Sectors
- Author Affiliations
- 1. Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- 2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- 3. Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
- 4. Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- 5. Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- 6. School of Pharmacy, University of Oslo, Oslo, Norway