Population pharmacokinetics of tacrolimus in paediatric haematopoietic stem cell transplant recipients: New initial dosage suggestions and a model based dosage adjustment tool
2009 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, no 4, 457-466 p.Article in journal (Refereed) Published
The population pharmacokinetics of tacrolimus was described in 22 paediatric haematopoietic stem cell transplant recipients and a model-based dosage adjustment tool that may assist with therapy in new patients was developed. Patients received tacrolimus by continuous intravenous infusion (0.03mg/kg/day) starting two days before transplantation, with conversion to oral therapy 2-3 weeks post-transplant. Population pharmacokinetic analysis was performed using NONMEM. A dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counter-balanced by the final population model, was created in Excel. Typical clearance was 106 mL/h/kg0.75, typical distribution volume was 3.71 L/kg and typical bioavailability was 15.7%. Tacrolimus clearance decreased with increasing serum creatinine and bioavailability decreased with post-operative day. Predictions from the model showed that current intravenous dose recommendations of 0.03 mg/kg/day may produce potentially toxic drug concentrations in the patient population, whereas current oral conversion of four times the adjusted intravenous dose may lead to subtherapeutic concentrations. We suggest a dose of 0.035mg/kg0.75/day to ensure satisfactory levels, and an oral conversion factor of six times the intravenous dose. A dosage adjustment tool was developed that is capable of suggesting an initial infusion rate based on patient weight and serum creatinine and of devising a further individualised dosage as individual drug concentration measurements become available. The tool also allows the clinicia to graphically examine the concentration-time profile of tacrolimus under different infusion rates, with or without a loading dose.
Place, publisher, year, edition, pages
Philadelphia PA, US: Lippincott Williams & Wilkins , 2009. Vol. 31, no 4, 457-466 p.
tacrolimus, pediatric hematopoietic stem cell transplant, population pharmacokinetics, Bayesian forecasting, dosage prediction
Research subject Pharmacokinetics and Drug Therapy
IdentifiersURN: urn:nbn:se:uu:diva-100505ISI: 000268567400006OAI: oai:DiVA.org:uu-100505DiVA: diva2:210449