British Journal of Cancer (2012) 107, 1100–1106 & 2012 Cancer Research UK All rights reserved 0007 – 0920/12 www.bjcancer.com Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents ,1 1 2 1 3 3 E Chatelut* , ML White-Koning , RHJ Mathijssen , F Puisset , SD Baker and A Sparreboom 1 2 EA 4553 Institut Claudius-Regaud, Universite´ de Toulouse, 20-24 rue du Pont St Pierre, 31052 Toulouse Cedex, France; Erasmus University Medical 3 Center – Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; St Jude Children’s Research Hospital, Memphis, TN, USA BACKGROUND: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient’s dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in Translational Therapeutics advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria. 2 2 2 2 METHODS: Three BSA bands were defined: BSAo1.7 m , 1.7 m pBSAo1.9 m , BSAX1.9 m and each patient dose was calculated 2 based on a unique BSA-value per band (1.55, 1.80, and 2.05 m , respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug. RESULTS: For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between À 14% and þ 22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; Po0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs. CONCLUSION: For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure. British Journal of Cancer (2012) 107, 1100–1106. doi:10.1038/bjc.2012.357 www.bjcancer.com Published online 28 August 2012 & 2012 Cancer Research UK Keywords: dose banding; dose standardisation; anticancer drugs; fixed dose; chemotherapy Drug dosing is a key issue in oncology due to the ‘dose–effect’ the current practice based on BSA dosing is associated with a large relationship of cytotoxics. The ideal (recommended) dose for a interindividual variability in terms of toxicity, largely due to specific patient is the highest dose associated with an acceptable heterogeneous plasma drug exposure between patients treated by toxicity. This dose is known as the maximum tolerated dose the same chemotherapy protocol. Unfortunately, for many anti- determined during the phase I trial. The current practice of using cancer drugs currently under use, little is known concerning the body surface area (BSA) in dosing anticancer drugs was characteristics that influence clearance (and consequently are implemented in clinical oncology half a century ago by Pinkel likely to affect individual AUC), and thus no satisfactory (1958). Based on the theory that large patients have a higher alternatives to BSA dosing have been suggested that could improve elimination capacity, it is assumed that those patients need to be the efficacy of these drugs. given higher doses than smaller patients to reach equal drug Dose banding has recently been suggested to optimise concentrations. Several studies have shown that both toxicity and chemotherapy preparation (Plumridge and Sewell, 2001; efficacy of cytotoxics are related to plasma drug exposure (i.e., area Pouliquen et al, 2011). Ranges (or bands) of BSA, and under the curve of the plasma drug concentrations vs time, AUC; corresponding mid-points of each band are predefined. The Gurney, 1996). Most of these studies and some others individual dose of a particular patient is calculated according to (Sparreboom, 2005) have shown that the only pharmacokinetic a single BSA-value per band, usually the mid-point of the BSA (PK) parameter significantly associated with individual AUC, band in which the actual BSA of the patient lies. Thanks to this elimination clearance (CL), is either poorly or not correlated with system chemotherapy provision can be rationalised and chemo- BSA for most cytotoxics (Reilly and Workman, 1993; Mathijssen therapies can be prepared in advance for drugs with sufficient et al, 2007). As a consequence of this poor or absent correlation, long-term drug stability. The main advantages of dose banding are to reduce patient waiting time and to improve capacity planning of *Correspondence: Dr E Chatelut; the pharmacy production, but additional benefits can also be E-mail: [email protected] found, such as reduced potential for medication errors, reduced Received 8 May 2012; revised 27 June 2012; accepted 17 July 2012; drug wastage, and prospective quality control of preparations. published online 28 August 2012 While the use of dose banding is unlikely to improve efficacy, it is Dose banding of cytotoxics E Chatelut et al 1101 of primary importance to evaluate whether it can be shown to be 75 mg m À 2. Blood samples were taken immediately before no worse than BSA dosing because of all the above-mentioned infusion, directly after infusion, and 30 min and 1, 2, 4, 7, 12, 24, advantages of this method. and 48 h post infusion. Concentrations of doxorubicin in plasma The objective of the present analysis was to compare BSA dosing were determined by HPLC with fluorescence detection (Rudek (as the current practice), dose banding, and fixed dose according et al, 2004). to PK criteria. By using individual values of clearance of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and Irinotecan Irinotecan was administered either alone or in topotecan) from a total of 1012 adult cancer patients, the AUCs combination with cisplatin as a 90-min continuous intravenous corresponding to each of these three dosing methods were infusion at a dose level between 175 and 350 mg m À 2 or at a flat compared with a target value of AUC for each drug. dose of 600 mg. Blood samples were collected before infusion, at 0.5 and 1.5 h during infusion, and 10, 20, and 30 min and 1, 2, 3, 3.5, 4, 5, 6.5, 10.5, 24, 30.5, 48, and 54.5 h after the end of infusion. PATIENTS AND METHODS Concentrations of irinotecan and its active metabolite SN-38 were Data collection determined by HPLC with fluorescence detection (de Jong et al, 2004). The study drugs included cisplatin (n ¼ 283), docetaxel (n ¼ 169), doxorubicin (n ¼ 103), irinotecan (n ¼ 187), paclitaxel (n ¼ 80), Paclitaxel Paclitaxel was supplied as a concentrated solution in and topotecan (n ¼ 190). These agents were considered because of cremophor-ethanol. The drug was administered as a single agent the known differences in their primary pathways of elimination. or in combination with carboplatin. Paclitaxel was administered All patients were at least 18 years old and provided written intravenously over 1, 3, or 24 h at doses ranging from 50 to informed consent for enrolment on studies approved by the local 225 mg m À 2. Blood samples were obtained at the following time review boards. Additional common eligibility criteria included: (a) points: immediately before infusion, and 0.5, 1, 1.5, 2, 2.5, 3, 5, 7, life expectancy of at least 12 weeks; (b) performance status of 0–2; 13, 25, 33, and 49 h after the start of paclitaxel infusion (1-h (c) no chemotherapy, hormonal therapy, or radiotherapy for at schedule); 1, 2, 3, 3.08, 3.25, 3.5, 4, 4.5, 5, 7, 9, 15, 21, 27, 35, and least 4 weeks before enrolment; (d) adequate contraception and a 51 h after the start of infusion (3-h schedule); or at 1, 22, 23, 23.92, negative pregnancy test result for women of childbearing age; and 24.08, 24.15, 25, 26, 27, 30, 36, and 45 h after the start of infusion (e) adequate bone marrow function, renal function, and hepatic (24-h schedule). Determination of total paclitaxel was performed function (i.e., patients with severe renal or hepatic impairment by HPLC with UV detection (Henningsson et al, 2005). were excluded). Simultaneous use of any medication, dietary supplements, or other compounds known to inhibit, induce, or Topotecan Topotecan was administered to patients once daily for otherwise affect the pharmacokinetics of the study drugs was not À 2 allowed. 5 consecutive days every 3 weeks (dose, 0.2–2.4 mg m or a fixed dose of 4 mg), once daily for 7, 10, 13, or 21 days (dose, 0.20–1.00 mg m À 2), or twice daily for 5, 10, or 21 days (dose, Sample collection and PK analysis 0.15–2.70 mg m À 2). The drug was administered as a single agent or in combination with cisplatin. Sample collection was performed Translational Therapeutics Preliminary PK data obtained from (subsets of) the studied patient before dosing, at 15 min after the start of infusion, immediately populations have been published previously for cisplatin (de Jongh before the end of infusion, and at 15 and 30 min and 1, 2, 3, 4, 6, 8, et al, 2001), docetaxel (Rudek et al, 2004), doxorubicin (Rudek and 10 h after the end of infusion.