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This study evaluated the influence of fludarabine on the pharmacokinetics of busulfan administered orally to patients receiving a conditioning regimen for hematopoietic allogeneic stem cell transplantation (HSCT). Twenty-six patients treated with oral busulfan (1 mg/kg/6 h for 4 days) were divided into two groups according to the concomitant administration of fludarabine (n = 11; 30 mg/m(2) for 5 days) or subsequent administration of cyclophosphamide (n = 15; 60 mg/kg for 2 days). Serial blood samples were collected on Day 4 of busulfan administration. Plasma busulfan concentrations were determined by HPLC-UV and the pharmacokinetic parameters were calculated using the WinNonlin program. Patients concomitantly treated with fludarabine showed reduced apparent clearance of busulfan (110.5 mL/h/kg vs. 157.4 mL/h/kg) and higher AUC0-6 (area under the plasma concentrations vs. time curve) than patients subsequently treated with cyclophosphamide (7.9 µg h/mL vs. 5.7 µg h/mL). No association was observed between busulfan AUC0-6 and clinical evolution of the patients. Although plasma busulfan concentrations were higher in patients receiving concomitant fludarabine, myelosuppression-related toxicity was less frequent than in patients treated with busulfan and cyclophosphamide. The results suggest that patients treated with fludarabine should receive 30% lower busulfan doses during conditioning protocols for HSCT., (© 2013, The American College of Clinical Pharmacology.)

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children., Competing Interests: Declaration of Conflicting Interests Dr McCune has received research funding from Otsuka Pharmaceutical of North America., (© The Author(s) 2013.)

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients < or = 12 kg should be dosed at 1.1 mg/kg and those > 12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

Chemotherapy for advanced ovarian cancer remains suboptimal. Despite the improvements in objective response rates realized with cisplatin-based combination chemotherapeutic regimens, most patients still die of refractory cancer. Drug resistance has emerged as the single most important determinant of treatment outcome. Laboratory studies have provided substantial insights into the cellular mechanisms of resistance to the commonly used chemotherapeutic agents. Decreased drug accumulation, metabolic drug inactivation, and repair or tolerance to drug-induced cellular injury all contribute to resistance at the cellular level. Identification of these mechanisms has facilitated the development of specific treatment strategies, many of which are in or nearing clinical trials. These strategies include dose intensification, inhibition of P-glycoprotein function, inhibition of cellular glutathione synthesis, and inhibition of cellular DNA repair. The initial results from clinical trials that use these strategies provide reasonable grounds for optimism. In addition, efforts to identify new drugs with activity against resistant cells continue. One such drug, taxol, has significant activity in tumors refractory to conventional therapy. These approaches offer hope that intensive laboratory and clinical efforts ultimately will translate into real improvements in the efficacy of chemotherapy for ovarian cancer.

Alkylating agents, natural products and platinum complexes are the primary chemotherapeutic agents used in the treatment of patients with ovarian cancer. Resistance frequently develops to all three classes of drugs and can be functionally separated into distinct biochemical pathways: (1) relative dose intensity plays a role in resistance to platinum complexes and to a lesser degree with alkylating agents; (2) induction of the membrane P-170 glycoprotein confers resistance to natural products and due to the potential usefulness of Taxol (a natural product extracted from the bark of yew trees), this mechanism of resistance may become more clinically relevant in the future; (3) increased levels of cellular glutathione (GSH) and glutathione S-transferases are important in the detoxification of alkylating agents and platinum complexes; and (4) increased DNA repair also is characteristic of resistance to platinum complexes and alkylating agents. Clinical trials have been initiated with agents that may inhibit the biochemical mechanisms of acquired drug resistance. Clinical trials are already in progress with alkylating agents combined with inhibition of GSH biosynthesis (i.e., buthionine sulfoximine) or enzymatic inhibitors of glutathione S-transferase activity (i.e., ethacrynic acid). Furthermore, the combination of aphidicolin, an inhibitor of DNA repair, together with platinum complexes also soon will be clinically tested based on promising results in preclinical models of ovarian cancer. Ovarian cancer is a disease of the elderly. Advances in the pharmacology of platinum compounds and in our understanding of the mechanisms of drug resistance should permit these patients to receive increasingly more effective chemotherapy.