E.Y.L. Blair(1), D.R. Mould(2), S.J. Clarke(3), L.P. Rivory(4), A.J. McLachlan(1)
(1)Faculty of Pharmacy, University of Sydney, Sydney, Australia; (2)Projections Research Inc, Phoenixville, PA, USA; (3)Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Australia; (4)Johnson and Johnson Research, Eveleigh, Australia
Objectives: The goals of this analysis were to develop a population pharmacokinetic/pharmacodynamic model that describes the relationship between patient exposure to raltitrexed and leucopenia and to identify covariates which may account for between patient variability in the PK/PD relationship.
Methods: All data modelling was performed with use of NONMEM v5.1.1 software. The pharmacokinetic study involved 112 adult patients (55% male) enrolled in 4 different Phase I clinical trials of raltitrexed as a single agent. Patients were given doses ranging from 0.1 to 4.5 mg/m2 every 3 weeks. A total of 2101 plasma concentration-time observations (average of 16 per patient) were available for at least 24 hours and up to 29 days for the first two cycles of raltitrexed treatment. The pharmacokinetic model was constructed using the first-order conditional estimation method with an interaction option. Model performance was assessed by evaluation of diagnostic plots and measures of parameter precision. The pharmacodynamic study involved 136 patients (56% male), of whom 102 patients were from the pharmacokinetic study. Exposure was measured as area under the plasma concentration time curve (AUC) and was estimated using the following formula: AUC=DOSE/CL where DOSE was the actual administered dose in each cycle. CL was estimated for patients without pharmacokinetic data using the formula for clearance and the patients’ relevant covariate information. Individual estimates of CL were used for patients with pharmacokinetic data. Adverse event data were collected up to 11 cycles of raltitrexed treatment. The exposure-leucopenia relationship was examined by a logistic regression analysis with use of the conditional Laplacian likelihood method.
Results: A linear 3-compartment model with an additive and proportional residual error model best described the data. Creatinine clearance and body weight were found to be determinants of raltitrexed clearance when evaluated as single covariates (OFV reduction of 37 and 26 respectively, P<0.0001). Creatinine clearance reduced 12% of the interpatient variability in clearance in the final model. The population mean clearance estimate was 2.5 +/- 0.2 L/h. The calculated raltitrexed AUC was found to be predictive of severity of leukopenia. Other covariates investigated (age, sex, body surface area, serum albumin levels, alanine aminotransferase, aspartate aminotransferase and total bilirubin levels) were not found to influence raltitrexed clearance or the predicability of leucopenia.
Conclusion: Patients with impaired renal function and low body weight can have a high raltitrexed exposure which may in turn lead to an increased risk of leucopenia. Careful monitoring of signs of toxicity in these patients is prudent.
References:
[1] Clarke SJ, Beale PJ, Rivory LP. Clinical and preclinical pharmacokinetics of raltitrexed. Clin Pharmacokinet 2000; 39: 429-443.
[2] Mould DR, Holford NHG, Schellens JHM, et al. Population pharmacokinetics and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther 2002; 71: 334-348.
Reference: PAGE 13 () Abstr 470 [www.page-meeting.org/?abstract=470]
Poster: poster