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Pharmacokinetics of Liposomal Cisplatin (Lipoplatin) in Combination with 5-FU in Patients with Advanced Head and Neck Cancer: First Results of a Phase III Study

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Pharmacokinetics of Liposomal Cisplatin (Lipoplatin) in Combination with 5-FU in Patients with Advanced Head and Neck Cancer: First Results of a Phase III Study ANTICANCER RESEARCH 27: 471-476 (2007) Pharmacokinetics of Liposomal Cisplatin (Lipoplatin) in Combination with 5-FU in Patients with Advanced Head and Neck Cancer: First Results of a Phase III Study C.F. JEHN1, T. BOULIKAS2, A. KOURVETARIS2, K. POSSINGER1 and D. LÜFTNER1 1Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie Charité, Campus Mitte, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin Charitéplatz 1, 10117 Berlin, Germany; 2Regulon, Inc., 715 N. Shoreline Blvd., Mt View, CA 94043, U.S.A. Abstract. Background: Lipoplatin, a novel liposomal the concentration time-curve (AUC) was less (6.5 Ìg/ml vs. 4.07 formulation of cisplatin, is composed of cisplatin and liposomes Ìg/ml and 66.85 Ìg/h/ml vs. 130.33 Ìg/h/ml, respectively). based on dipalmityl phosphatidyl glycerol (DPPG), soy Conclusion: The pharmacokinetic profile of lipoplatin (in phosphatidyl choline (SPC-3), cholesterol and methoxypoly- combination with 5-FU) suggests that the liposomal formulation ethylene glycol-distearoyl phosphatidylethanolamine (mPEG2000- results in a greater body clearance and shorter half life than DSPE). Liposomal encapsulation of cisplatin is designed to conventional cisplatin, which confirms the clinical observation of increase safety and tolerability by decreasing, e.g., nephrotoxicity decreased toxicity, especially renal deterioration. through decreased exposure of organs to cisplatin, while effectively delivering the drug to the tumor. In an ongoing phase III trial Cisplatin is one of the most active chemotherapeutic agents comparing cisplatin to lipoplatin (both in combination with used in the treatment of advanced squamous cell carcinoma infusional high-dose 5-Fluoruracil) in advanced head and neck of the head and neck (SCCHN). However, its clinical cancer (HNC), a sub-study to determine the pharmacokinetic efficacy is contrasted by its toxicity profile. In particular profile of lipoplatin in comparison to conventional cisplatin was renal toxicity, peripheral neuropathy and hematotoxicity undertaken. Materials and Methods: In total, twelve patients with limit its clinical use and a cumulative effect of successive advanced HNC received a combination chemotherapy with either doses is apparent (1). lipoplatin/5-FU or cisplatin/5-FU. Plasma samples were analyzed The application of liposomes as drug carriers offers the for concentration of total platinum in patients from both arms. possibility to manipulate the pharmacokinetics of drugs and to Results: All twelve patients from the pharmacokinetic sub-study improve their efficacy and reduce toxicity (2). Lipoplatin is a were male Caucasians at a mean age of 60 years. There was no liposomal formulation of cisplatin. The anionic lipid dipalmityl difference in age or kidney function between the two treatment phosphatidyl glycerol (DPPG) gives lipoplatin its fusogenic groups. The total body clearance for cisplatin was 1.25 L/(hxm2) properties in the liposomal formulation. These nanoparticles for the liposomal formulation, compared to 0.62 L/(hxm2) for (110 nm) extravasate preferentially into solid tumors and their conventional cisplatin. The terminal half life was half as long for metastases through the altered, leaky vasculature. The lipoplatin (10.98 h) as compared to cisplatin (24.5h). Even entrance of lipoplatin particles into the kidney tubule cells is though the maximum observed concentration in the plasma limited as a fusion of the lipid capsule with the cell membrane (Cmax) was greater for lipoplatin than for cisplatin, the area under is needed for reactivity (3). Through this mechanism the release of cisplatin into the system is reduced and the toxic side-effects are decreased. Animal studies show five times lower levels of platinum in kidneys after a lipoplatin infusion Correspondence to: PD Dr. med. Diana Lüftner, Medizinische compared to cisplatin treatments at equal dosing (4). Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie To test the efficacy and toxicity profile in a clinical setting a Charité, Campus Mitte, Universitätsmedizin Berlin, Humboldt- subprotocol to a randomized, multicenter phase III trial of Universität zu Berlin Charitéplatz 1, 10117 Berlin, Germany. Tel: SCCHN was designed, in which conventional cisplatin or the +49 30 450 55 32 59, Fax: +49 30 450 51 39 19, e-mail: [email protected] / [email protected] liposomal formulation of cisplatin (lipoplatin) was used in combination with 5-FU. The total platinum concentration was Key Words: Liposomal cisplatin, lipoplatin, 5-fluorouracil, head and measured in both arms of the study following administration neck cancer. of either cisplatin (and 5-FU) or lipoplatin (and 5-FU). 0250-7005/2007 $2.00+.40 471 ANTICANCER RESEARCH 27: 471-476 (2007) Table I. Patient characteristics relevant for the pharmakokinetic and Table II. Mean and standard deviation of the pharmacokinetic pharmakodynamic evaluations. parameters of lipoplatin vs. conventional cisplatin. Parameter Lipoplatin Cisplatin T-test Parameter (unit) Lipoplatin CV% Cisplatin CV% T-test Dose (mg/m2) 100 100 AUC (Ìg/h/ml) 66.9±39.5 59 130.3±69.4 53 NS C (Ìg/ml) 6.5±4.5 67 4.1±2.1 52 N.S. Dosing interval day 1, 8 15 q3w day 1 q3w max MRT (h) 15.9±7.7 49 35.4±14.5 41 p<0.05 Male/female 6/0 6/0 kel (h–1) 0.1±0.07 29 0.03±0.01 33 p<0.01 Age (years) 59.2±5.0 61.2±7.2 N.S. tó (h) 11.0±5.4 49 24.5±10.1 41 p<0.05 2 Height (cm) 178.5±3.8 174,.7±5.4 CL L/(h x m ) 1.3±0.6 46 0.6±0.3 47 p<0.05 Vss (L/m2) 15.2±5.4 35 18.3±3.1 17 N.S. Weight (Kg) 71.6±13.4 62.9±9.8 CrCl (ml/min) 93.73±16.5 91.1±27.4 N.S. AUC=area under the curve; Cmax=maximum concentration; kel=elimination constant; tó=half life; CL=clearance; Vss=steady N.S.=not significant; CrCL: Creatinin clearance. state; CV=coefficient of variation, MRT=mean residence time Materials and Methods follows: wavelength 265.9 nm; slit width (nm) 0.2 L; read time 4 sec; injected sample volume 20 Ìl; furnace temperature escalation Plasma samples for pharmacokinetic evaluation were collected program 6 steps –90ÆC, 100ÆC, 300ÆC, 450ÆC, 1400ÆC and 2650ÆC. during the first and second cycles of treatment only. This study was approved by the institutional review board and all patients signed Statistical analysis. Estimates of pharmacokinetic parameters were informed consent forms. obtained by non-compartimental analysis, based on statistical Only patients with histologically confirmed SCCHN (primary moment theory (6, 7). These parameters are determined by a metastatic or patients with relapsed/progressive disease) between numerical integration procedure such as the trapezoidal rule which the age of 18-75 years with sufficient renal function defined as was employed to determine the plasma AUC. The mean residence creatinine clearance >50 ml/min where included in the study. time (MRT) was calculated from the equation MRT=AUMC/AUC, After stratification (criteria: primary metastatic disease, where AUMC is the area under the first moment curve, and MRT recurrent or progressive SCCHN, prior chemotherapy/no prior represents the time for 63.2% of the administered dose to be chemotherapy, prior cisplatin-based chemotherapy/prior non- eliminated. 1/Kelim (elimination rate constant) is the MRT, the cisplatin based chemotherapy and center), patients were statistical moment analogue to half-life tó. The tó (elimination half- randomized between the following arms: Arm A: patients life) was calculated form the formula tó=0.693 x (1/Kelim). The CL received 100 mg/m2/d lipoplatin (d 1,8,15) plus 1000 mg/mÇ/d 5- value was calculated from CL=Di.v./AUC, where Di.v. is the FU (d 1-5 continuous infusion) every three weeks for six cycles; intravenous dose of lipoplatin/cisplatin and AUC the relative area arm B: patients received 100 mg/m2/d cisplatin (d 1) plus 1000 under the curve. The Vss was calculated form the formula mg/m2/d 5-FU (day 1-5 continuous infusion) every three weeks Vss=(infused dose x AUMC/AUC2)-(infused dose x T/(2xAUC), for six cycles. The main endpoints for this pharmacokinetic where T is the infusion time. Creatinin clearance (CrCl) was analysis were the maximum observed concentration in the plasma estimated by the method of Trollfors et al. (8). The statistical significance of differences between the (Cmax), the terminal half-life (tó), the area under the concentration-time curve (AUC), the total body clearance (CL) pharmacokinetic parameters of lipoplatin and cisplatin were and the volume of distribution at steady state (Vss). Each evaluated by using the unpaired 2-sample T-test with a significance variable was recorded for total platinum. level of 0.05 (2-tailed). The T-test for unequal variances was used in cases where the F-test for variances showed group variances to Pharmacokinetic sampling. For drug concentration assays, 10 ml of be unequal. All results were reported as mean±standard deviation blood was collected in tubes containing EDTA. Samples were (SD). As statistical software SPSS 12.00 was used. collected at 0, 2, 4, 8, 12, 24, 48 and 120 h after the start of the IV infusion of lipoplatin (infusion duration of 4h) and cisplatin Results (infusion duration of 1h). The 5-FU continuous infusion (day 1-5) was initiated directly after these infusions were completed. Plasma Pharmacokinetic measurements were performed on twelve samples were diluted with water before the analytic procedures. patients (six patients from the lipoplatin arm and six patients from the cisplatin arm). As shown in Table I, all GF-AAS (Graphite Furnace Atomic Absorption Spectrometry) assay. subjects were male and showed no significant difference in Total platinum concentrations were determined in plasma using a age or renal function as measured by the CrCl.
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