Population Pharmacokinetic of Oral Busulfan in Japanese Undergoing Hematopoietic Stem Cell Transplantation.

We previous evaluated busulfan (BU) pharmacokinetics (PK) in seven Japanese adult patients who underwent allogenic hematopoietic stem cell transplantation (HSCT) at Fukuoka University Hospital. We showed that the average plasma BU concentrations at steady state (Css) ranged from 745 to 2422 ng/mL. BU population PK (PPK) parameters for Caucasian have already been reported. However, few data are available for Asian people.

We therefore investigated the PPK parameters of BU in 82 Japanese adult patients (51 males and 31 females) who underwent HSCT following a BU-containing conditioning regimen. Their average age was 43.4 years, ranging from 16 to 68 years. Blood samples were collected in heparinized tubes at 0.5,1,2,4 and 6 hours after the oral administration of BU, and the plasma BU concentrations were measured by high performance liquid chromatography (HPLC). A one compartment open model with first-order absorption was used. We estimated individual BU doses by using Bayesian, and PK parameters by using nonlinear mixed effects modeling (NONMEM) computer program.

Since Oral clearance (L/h/kg) (CL/F) and distribution volumes (L/kg) (Vd/F) were proportional to total body weight, so we set the following formulas. The final PPK parameters were CL/F = 0.139•TBW•1.14^GEN •1.09^VPA •1.52^TBIL≥1.2, Vd/F = 0.76•TBW•0.902^GEN, absorption rate constant (h⁻¹) (ka) = 2.58. TBW is total body weight (kg), VPA = 1 for concomitant administration of valproic acid and 0 for another anticonvulsant, GEN = 1 for patients gender female and 0 for male, TBIL≥1.2 = 1 for total bilirubin above 1.2 mg/dL and 0 for below.

CL/F in Japanese and Caucasian were 0.139 and 0.149, respectively, Vd/F were 0.76 and 0.64, respectively, and ka were 2.58 and 1.68, respectively.

These data showed that CL/F and Vd/F were almost same between Japanese and Caucasian, but ka was larger. We also found that high serum levels of total bilirubin and administration of VPA induced the increase of CL/F at 52 % and 9 %, respectively. The interindividual variabilities in CL/F, Vd/F and ka were 21.9%, 20.9% and 82.3%, respectively, and the residual variability was 18.4% as coefficient of variation.

This study represented that oral BU PPK parameters in Japanese were different from that in Caucasian. BU PPK parameters were influenced by gender, serum levels of total bilirubin and administration of VPA. Our study showed that BU PPK differed between Japanese and Caucasian.