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Accuracy, feasibility and clinical impact of prospective Bayesian pharmacokinetically guided dosing of cyclophosphamide, thiotepa and carboplatin in high‐dose chemotherapy
Author(s) -
Jonge M. E.,
Huitema A. D.,
Tukker A. C.,
Van Dam S. M.,
Rodenhuis S.,
Beijnen J. H.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.252
Subject(s) - carboplatin , medicine , dosing , thiotepa , pharmacokinetics , toxicity , population , pharmacology , cyclophosphamide , chemotherapy , urology , cisplatin , environmental health
Background Relationships between toxicity and pharmacokinetics (PK) have been demonstrated for cyclophosphamide (CP), thiotepa (TT) and carboplatin (CA) in high‐dose chemotherapy (CTC). We prospectively evaluated whether variability in exposure to CP, TT and CA, and their activated metabolites, can be decreased with PK‐guided dose administration, and evaluated its clinical effect. Methods Patients received multiple 4‐day courses of CP (1000–1500 mg/m 2 /day), TT (80–120 mg/m 2 /day) and CA (AUC 3.3–5 mg*min/ml/day). Doses were adapted on day 3 based on PK‐analyses of CP, 4‐hydroxycyclophosphamide, TT, tepa and CA performed on day 1, using a Bayesian algorithm. Doses were also adjusted before and during 2 nd and 3 rd courses. Observed toxicity was compared with that in patients receiving standard dose CTC (n=43). Results 46 patients (108 courses) were included. For CP, TT and CA, a total of 39, 58 and 65 dose adaptations were performed within courses and 17, 40 and 43 before courses. The precision within which the target exposure was reached improved compared with no adaptation, especially after within‐course adaptations (precision for CP, TT and CA: 19, 16 and 13%); >85% led to an exposure within ±25% of the target, compared to 60% without dose adjustments. Toxicity was similar to that in a reference population, although, the incidence of veno‐occlusive disease was reduced. Conclusions Bayesian PK‐guided dosing for CP, TT and CA was feasible and led to a marked reduction in variability of exposure. Clinical Pharmacology & Therapeutics (2005) 77 , P94–P94; doi: 10.1016/j.clpt.2004.12.252