Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites

Esther Oyaga-Iriarte1, Asier Insausti2, Lorea Bueno2, Onintza Sayar2, Azucena Aldaz3

1Pharmamodelling SL, Pamplona, Spain.
2Pharmamodelling SL, Pamplona, Spain
3Service of Hospital Pharmacy, Clinica Universidad de Navarra, Pio XII 36, Pamplona, Spain.

Abstract


Purpose: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. Methods: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. Results: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. Conclusions: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases.


J Pharm Pharm Sci, 22 (1): 112-121, 2019

Full Text:

PDF

References


Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, et al. Comparison of Oral Capecitabine Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Treatment in 605 Patients With Metastatic Colorectal Cancer: Results of a Randomized Phase III Study. J Clin Oncol. 2001;19(8):2282–92. DOI: 10.1200/JCO.2001.19.8.2282

Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, et al. Oral Capecitabine compared with intravenous Fluorouracil Plus Leucovorin in Patients With Metastatic Colorectal Cancer : Results of a Large Phase III Study. J Clin Oncol. 2001;19(21):4097–106.

Rea DW, Nortier JWR, Ten Bokkel Huinink WW, Falk S, Richel DJ, Maughan T, et al. A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol. 2005;16(7):1123–32. DOI: 10.1093/annonc/mdi227

Walko CM, Lindley C. Capecitabine: A Review. Clin Ther. 2005;27(1):23–44. DOI: 10.2307/2678832

Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5 fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998;34(8):1274–81. DOI: 10.1016/S0959-8049(98)00058-6

Gieschke R, Burger H, Reigner B, Blesch KS, Steimer J. Population pharmacokinetics and concentration–effect relationships of capecitabine metabolites in colorectal cancer patients. Clin Pharmacol. 2003;55(November 2001):252–63.

Gerbrecht BM. Current Canadian experience with capecitabine: Partnering with patients to optimize therapy. Cancer Nurs. 2003;26(2):161–7. DOI: 10.1097/00002820-200304000-00011

Gieschke R, Reigner B, Blesch KS, Steimer JL. Population pharmacokinetic analysis of the major metabolites of capecitabine. J Pharmacokinet Pharmacodyn. 2002;29(1):25–47. DOI: 10.1023/A:1015716617967

Zandvliet A, Siegel-Lakhai W, Beijnen J, Copalu W, Etinne-Grimaldi M, Milano G, et al. PK/PD model of indisulam and capecitabine: interaction causes excessive myelosuppression. Clin Pharmacol Ther. 2008;83(6):829–39. DOI: 10.1038/sj.clp

Urien S, Rezaï K, Lokiec F. Pharmacokinetic modelling of 5-FU production from capecitabine - A population study in 40 adult patients with metastatic cancer. J Pharmacokinet Pharmacodyn. 2005;32(5–6):817–33. DOI: 10.1007/s10928-005-0018-2

D’Argenio DZ. Optimal Sampling Times for Pharmacokinetic Experiments. J Pharmacokinet Biopharm. 1981;9(6).

Hirzel A, Guisan A. Which is the optimal sampling strategy for habitat suitability modelling. Ecol Modell. 2002;157:331–41.

Zufía L, Aldaz A, Giráldez J. Simple determination of capecitabine and its metabolites by liquid chromatography with ultraviolet detection in a single injection. J Chromatogr B Anal Technol Biomed Life Sci. 2004;809(1):51–8. DOI: 10.1016/j.jchromb.2004.06.004

Beal S, Sheiner L, Boeckmann A, Bauer R. NONMEM User’s Guide. 1998.

Gilks W, Richardson S, Spiegelhalter D. Markov Chain Monte Carlo in Practice. New York: Chapman and Hall/CRC.; 1996. 1-512 p.

Dumont C, Lestini G, Le Nagard H, Mentré F, Comets E, Nguyen TT. PFIM 4.0, an extended R program for design evaluation and optimization in nonlinear mixed-effect models. Comput Methods Programs Biomed. 2018;156:217–29. DOI: 10.1016/j.cmpb.2018.01.008

Woillard JB, Debord J, Monchaud C, Saint-Marcoux F, Marquet P. Population Pharmacokinetics and Bayesian Estimators for Refined Dose Adjustment of a New Tacrolimus Formulation in Kidney and Liver Transplant Patients. Clin Pharmacokinet. 2017;56(12):1491–8. DOI: 10.1007/s40262-017-0533-5

Flint RB, ter Heine R, Spaans E, Burger DM, de Klerk JCA, Allegaert K, et al. Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns. Eur J Clin Pharmacol. 2018;In press. DOI: 10.1007/s00228-018-2529-y

Jia Y, Meng XU, Li YAN, Xu C, Zeng WEN, Jiao Y, et al. Optimal sampling time‑point for cyclosporin A concentration monitoring in heart transplant recipients. Exp Ther Med. 2018;16:4265–70. DOI: 10.3892/etm.2018.6711

Blesch KS, Blesch KS, Gieschke R, Gieschke R, Tsukamoto Y, Tsukamoto Y, et al. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience. Invest New Drugs. 2003;21(2):195–223. DOI: 10.1023/A:1023525513696

Wade JR, Kelman AW, Howie CA, Whiting B. Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. J Pharmacokinet Biopharm. 1993;21(2):209–22. DOI: 10.1007/BF01059771

Bauer RJ, Dedrick RL, White ML, Murray MJ, Garovoy MR. Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis. J Pharmacokinet Biopharm. 1999;27(4):397–420. DOI: 10.1023/A:1020917122093

Wählby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci. 2002;4(4):68–79. DOI: 10.1208/ps040427

Schellens HM, Webster K, Rorer P, Raymond A, France PB, Maccallum P. Optimal Sampling Clearance Strategies for Bayesian Estimation of Docetaxel. Clin Cancer Res. 1997;3(September):1535–8.




DOI: http://dx.doi.org/10.18433/jpps30392