Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients.
The aims of the present study were (1) to investigate and quantify the pharmacokinetics, including inter-occasion variability and covariate relationships, of busulphan in BMT patients and (2) to develop a user-friendly initial dosing and therapeutic drug monitoring (TDM) strategy for the treatment of those patients with busulphan. The pharmacokinetics of busulphan was studied in 64 adults and 12 children who received busulphan (1 mg/kg) four times daily for 4 days. A one-compartment model with first order absorption and a lag time was sufficient in describing the concentration-time profile. Oral clearance (CL/F) was found to be correlated to weight (+1.2%/kg), ALT (-13%/microcat/l) and concomitant phenytoin treatment (+21%). CL/F and the volume of distribution (V/F) were estimated to 9.23 l/h and 39.3 l, respectively, in a typical individual. Inter-occasion variability (9.4%) in CL/F was estimated to be less than inter-individual variability (28%), a prerequisite for the value of TDM. Bayesian CL/F estimates based on three samples were in good accordance with those based on all samples. The final population model was implemented into the program Excel. The resulting flexible and easy to use dosing program might be used for both initial and, requiring only three plasma samples, maintenance dose individualization of busulphan therapy.
Sandström
M
M
Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Faculty of Pharmacy, Uppsala University, S-751 25 Uppsala, Sweden.
Karlsson
M O
MO
Ljungman
P
P
Hassan
Z
Z
Jonsson
E N
EN
Nilsson
C
C
Ringden
O
O
Oberg
G
G
Bekassy
A
A
Hassan
M
M
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D001825:Body Fluid Compartments; D001835:Body Weight; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002998:Clonazepam / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D019172:Transplantation Conditioning / Q000379:methods*; D014584:User-Computer Interface; D014916:Whole-Body Irradiation
D000927:Anticonvulsants; D018906:Antineoplastic Agents, Alkylating; D002998:Clonazepam; D010672:Phenytoin; D002066:Busulfan