title: Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer patients based upon total platinum measurement in plasma.
abstract: Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)/pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma. Nineteen patients (66 therapeutic courses) were treated with platinum-based combinational therapy. Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent prospective dose adjustment in order to reach a target Cmax (Cend) of 1.95 mg/L of total platinum. Performance of the Bayesian dosing method was evaluated by comparing target Cmax with achieved Cmax. The mean+/-SD Cmax achieved was 1.93+/-0.16 mg/L. No statistically significant difference was observed between experimental and target values (P>0.05, t test), and Cend achievement was done with an overall 6.6% precision, a performance to be compared with the initial 54% interpatient variability observed in CDDP clearance. A nonlinear mixed effect model population PK analysis was subsequently performed to identify retrospectively the covariates associated with PK parameters of total CDDP. It showed a good correlation (r=0.84, P=0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r=0.59) was found between BSA and total CDDP clearance and, importantly, no additional relationship was established with BSA when successive therapeutic courses, and not only the first one, were considered. This highlights the critical importance of total drug accumulation on CDDP pharmacokinetics when several infusions are to be administered in a row and, therefore, the need for real-time dose individualization that takes into account the course number, rather than BSA. Finally, doses of CDDP administered during each course were significantly higher (+20%, P<0.01) than the ones classically normalized with BSA, thus leading to an overall greater drug exposure in the patients. It is noteworthy that despite these markedly higher doses, little severe toxicity was reported, and all of the patients presented in this study were still alive and disease free after a follow-up of up to 15 years.
authors.affiliation: Medical Oncology Unit, Clinical Pharmacokinetics Unit, La Timone University Hospital, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Salas
authors.forename: Cédric
authors.initials: C
authors.lastname: Mercier
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Bertrand
authors.initials: B
authors.lastname: Pourroy
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Fanciullino
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tranchand
authors.forename: Suzanne
authors.initials: S
authors.lastname: Monjanel-Mouterde
authors.forename: Marjorie
authors.initials: M
authors.lastname: Baciuchka-Palmaro
authors.forename: Charlotte
authors.initials: C
authors.lastname: Dupuis
authors.forename: Chenguang
authors.initials: C
authors.lastname: Yang
authors.forename: Medhi
authors.initials: M
authors.lastname: Balti
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.forename: Alain
authors.initials: A
authors.lastname: Durand
authors.forename: Roger
authors.initials: R
authors.lastname: Favre
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001499:Bayes Theorem; D001830:Body Surface Area; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004066:Digestive System Diseases / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007260:Infusion Pumps; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007677:Kidney Function Tests; D007984:Leydig Cell Tumor / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015233:Models, Statistical; D012189:Retrospective Studies; D016019:Survival Analysis; D013736:Testicular Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin