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Objectives: High-dose chemotherapy with cyclophosphamide (CP), thiotepa (TT) and carboplatin (CA) (CTC) can be complicated by the occurrence of severe toxicities such as mucositis, veno-occlusive disease of the liver (VOD), hemorrhagic cystitis, oto- and cardiotoxicity. Variability in occurrence of these toxicities may be due to substantial differences in pharmacokinetics of CP, TT and CA between individuals, resulting in markedly different exposures, as expressed by the area under the plasma concentration-time curve (AUC), to the individual drugs and their metabolites in patients treated at the same dose levels. Relationships between toxicity and pharmacokinetics have been demonstrated in CTC chemotherapy [1]. The aim of our prospective study was to evaluate whether variability in exposure to CP, TT and CA, and their relevant activated metabolites, can be decreased with pharmacokinetically guided dose administration. Moreover, the clinical effect of targeted drug dosing in comparison with conventional dosing was evaluated.

 Methods: Patients received single or multiple courses of high CP (1000 or 1500 mg/m²/day), TT (80 or 120 mg/m²/day) and CA (dose calculated using the Calvert formula with 13.3 or 20 mg*min/ml as target AUC) for four consecutive days. Standard doses were administered on day one and two of the first course. Doses of all three compounds were adapted on day three based on pharmacokinetic analyses of CP and its active metabolite 4-hydroxycyclophosphamide (4OHCP), TT and its metabolite tepa (T) [2] and ultrafilterable CA performed on day one. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, using previously developed population pharmacokinetic models developed with NONMEM [3]. This dosing strategy was designed to obtain a pre-specified whole-course target AUC of 4OHCP (105 or 140 µM*h), a combined target AUC of TT and T (276 or 367 µM*h), and a target AUC of ultrafilterable CA (13.3 or 20 mg*min/ml). On day three or four pharmacokinetic samples were obtained to evaluate the dose adjustment. Dose adjustments were also carried out before and during second and third courses based on the findings of previous courses. Observed toxicity was compared with the toxicity in a similar historical patient population who received standard dose CTC (n=43).

Results: A total of 46 patients (108 courses) were included in the study. For CP, TT and CA, respectively, a total number of 39, 58 and 65 dose adaptations were performed within courses and 17, 40 and 43 before start of a second or third course. After pharmacokinetically guided dose adaptations, the precision within which the target exposure was reached improved compared with no adaptation, especially after adaptations during a course (for CP, TT and CA, precision after within-course adaptations: 19, 16 and 13%; precision after between-course adaptations 19, 32 and 19%, respectively). More than 85% of the dose adjustments for all agents led to an exposure within ±25% of the target, compared to 60% when no dose adjustments were performed. Exposures >50% above the target were successfully prevented since all patients who would have had these exposures were within 35% of the target after within-course dose adjustment. The occurrence of mucositis, neuropathy, ototoxicity, cardiotoxicity and hemorrhagic cystitis in this population was similar to that observed in a reference population, however, no cases of VOD were seen in patients with CP dose adaptations, compared with 4 cases in the reference population.

Conclusion: The Bayesian pharmacokinetically guided dosing strategy for CP, TT and CA in the CTC regimen was feasible and led to a marked reduction in variability of exposure, especially when dose adaptations were performed within the short time-span of a 4-day course. Extremely high and low exposures were prevented successfully. More patients should be included to draw significant conclusions on the clinical impact of the dosing strategy.

References:
[1] ADR Huitema, M Spaander, RAA Mathôt, MM Tibben, MJ Holtkamp, JH Beijnen, S Rodenhuis. Relationship between exposure and toxicity in high-dose chemotherapy with cyclophosphamide, thioTEPA and carboplatin. Ann Oncol 2002; 13: 374-384.
[2] ME de Jonge, ADR Huitema, S Rodenhuis, JH Beijnen. Integrated population pharmacokinetic model of both cyclophosphamide and thiotepa suggesting a mutual drug-drug interaction. J Pharmackinet Pharmacodyn 2004; 31: 135-156
[3]  ME de Jonge, SM van Dam, MJX Hillebrand, H Rosing, ADR Huitema, S Rodenhuis, JH Beijnen. Simultaneous quantification of cyclophosphamide, 4-hydroxycyclophosphamide, N,N’,N’’-triethylenethiophosphoramide (thiotepa) and N,N’,N’’-triethylenephosphoramide (tepa) in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-MS/MS). J Mass Spectrom 2004; 39: 262-271