Relationships between body composition parameters and fluorouracil pharmacokinetics Milena Gusella, Sivia Toso, Eros Ferrazzi, Mariano Ferrari & Roberto Padrini Department of Pharmacology and Anaesthesiology and Department of Clinical and Experimental Medicine, University of Padova, Padova and Oncology Division, Rovigo Hospital, Rovigo, Italy
Aims To verify whether fluorouracil (FU) clearance (CL) and volume of distribution (Vss) are better correlated with specific body compartments, such as body cell mass (BCM), total body water (TBW) or fat free mass (FFM), rather than with body surface area (BSA) or total body weight (BW). Methods Thirty-four patients (13 females and 21 males) affected by colorectal cancer and receiving FU as adjuvant therapy entered the study. CL and Vss were determined after a 2 min i.v. injection of FU (425 mg mx2) and leucovorin (20 mg mx2). Body composition, in terms of BCM, TBW and FFM, was evaluated non-invasively by bioelectrical impedance analysis (BIA). Results Significant but poor correlations were found between CL or Vss and most anthropometric parameters, including BIA-derived measures (r 2 range=0.10–0.21). However, when multiple regression analysis was performed with sex, TBW and FFM as independent variables, the correlations improved greatly. The best correlation was obtained between CL and sex (r2=0.44) and between Vss and sex (r2=0.36). FFMnormalized CL was significantly higher in women than in men (0.030t0.008 vs 0.022t0.005 l minx1 kgx1; 95% CI of difference 0.012, 0.003; P=0.003), suggesting that FU metabolism is more rapid in females. Surprisingly, Vss was highly correlated with CL (r2=0.67; CL=0.52+Vssr0.040). This finding may either be explained by extensive drug metabolism in extra-hepatic organs or by variable inactivation on first-pass through the lung. Both these hypotheses need experimental validation. Conclusions The pharmacokinetics of FU are better predicted by FFM and TBW than by standard anthropometric parameters and predictions are sex-dependent. The use of BIA may lead to improved dosing with FU. Keywords: bioelectrical impedance analysis, fluorouracil, pharmacokinetics
Introduction Fluorouracil (FU) is still used to treat a variety of solid tumours and in particular, in combination with leucovorin, is the standard treatment for adjuvant chemotherapy of colorectal cancer [1]. One major hindrance to optimizing treatment with FU is its considerable interpatient pharmacokinetic variability, which leads to unpredictable
Correspondence: Roberto Padrini, Dipartimento di Farmacologia e Anestesiologia, Largo Meneghetti 2, 35131 Padova, Italy. Tel.: +39-0498275777; Fax:+39-049-8275093; E-mail:
[email protected] Received 5 June 2001, accepted 4 March 2002.
f 2002 Blackwell Science Ltd Br J Clin Pharmacol, 54, 131–139
plasma drug concentrations [2, 3]. In humans, more than 80% of an i.v. dose of FU is eliminated from the body via reductive metabolism by dihydropyrimidine dehydrogenase (DPD) [4]. Plasma drug clearance is highly variable and depends on dose, exhibiting saturation kinetics [5], time of day [6] and administration schedule (i.v. bolus or prolonged infusion) [7]. Even when the drug is given under standardized conditions, namely at the same dose, infusion duration, time of day, a large interindividual variability in clearance has been reported [8]. Pharmacokinetic-pharmacodynamic correlation studies have shown that, following continuous 5FU i.v. infusion, clinical response and/or toxicity are related to the area under the plasma concentration vs time 131
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curve (AUC) [3] and that individual FU dose adjustment with pharmacokinetic monitoring provides high response and survival rates associated with good tolerability [9]. Although the usefulness of monitoring FU AUC following i.v. bolus administration has not yet been established, preliminary findings from our laboratory [10] suggest that a correlation between AUC and FU toxicity does exist. Factors, such as sex, age and DPD activity in peripheral blood mononuclear cells, have been shown to be correlated with FU clearance, but these relationships are generally weak, such that most variability in clearance remains unexplained [3]. Although FU is a hydrophilic drug (octanol/water partition coefficient=0.1) [11], it passes across biological membranes easily by saturable active transport [12], thus reaching its sites of action and elimination. Since FU plasma clearance after prolonged i.v. infusion largely exceeds liver blood flow and even cardiac output, its metabolism must also occur in extra-hepatic tissues [13]. On the basis of these considerations, FU clearance and volume of distribution are probably related to body composition, particularly body cell mass (BCM), fat free (lean) mass (FFM) and total body water (TBW). BCM, FFM and TBW can be estimated by bioelectrical impedance analysis (BIA), a noninvasive technique which measures the resistance (R) and reactance (Xc) of the body to the flow of a low-voltage alternating current [14, 15]. The aims of our study were to assess whether body composition parameters as assessed by BIA are correlated with FU clearance and volume of distribution, and whether this correlation is strong enough to permit a better prediction of FU pharmacokinetic parameters than that obtained with standard anthropometric measures, namely body weight and body surface area.
Methods Patients Thirty-four patients (21 males, 13 females), aged between 45 and 80 years and diagnosed with colorectal cancer (Dukes class: B2-C) took part in the study, after giving their written informed consent. All of them had a normal hydration status. After radical surgery, they started adjuvant chemotherapy in which FU (425 mg mx2) and leucovorin (20 mg mx2) were administered by rapid (2 min) intravenous injection daily for 5 days, for six consecutive cycles every 4–5 weeks [16]. The study was performed on the 2nd day of the 1st therapy cycle, between 14.00 and 15.00 h. The main demographic characteristics of each patient (age, sex, body weight, surface area) were recorded. Body surface area (BSA) was calculated by means of the formula of Haycock [17]: BSA=body weight0.5378rheight0.3964r0.024265. 132
The study procedure was approved by the Ethics Committee of the Hospital of Rovigo.
BIA measurements BIA measurements were performed 15 min before FU administration. After cleaning the skin with alcohol, two pre-gelled electrodes were cut in half and placed on the dorsal surface of the right hand and right foot. Two were current-introducing electrodes which were placed 5–6 cm distal to two voltage-sensing electrodes. Lowintensity (800 mA), single-frequency alternating current (50 KHz) was delivered through a BIA 101 analyser (Akern Srl, Firenze, Italy, on licence from RJL System, Detroit, USA) and the two primary impedance components, resistance (R) and reactance (Xc), were measured. Total body water (TBW), fat free mass (FFM) and body cell mass (BCM) were then calculated from body weight, height, age, sex, R and Xc, using software provided by Akern Srl (BODYGRAM Y2K, version 2000 [18]. This method of estimating body composition parameters has been validated by Kotler et al. [15] for middle-aged people and by Deurenberg et al. [19] for elderly subjects (>60 years).
H.p.l.c. analysis of FU The drug was extracted from 0.5 ml plasma with ethylacetate (8 ml) after adding 0.5 ml of a Na2SO4 solution (200 g lx1) and 50 ml of Na acetate buffer (pH 4.7), using 5-bromouracil as internal standard. The dried residuum was reconstituted with 300 ml water, and 50 ml were injected onto a LiChroCART 125–41 column (Merk) packed with Superspher 60 PR-8 and kept at 50u C, using freshly distilled water as the mobile phase (flow rate: 1 ml minx1; Waters 515 HPLC pump). Analytes were detected at 254 nm (Waters, 2487 dual l absorbance u.v. detector). The lowest detection limit was 20 ng mlx1 and intraday and interday coefficients of variation were 4.5% and 6.1%, respectively.
Pharmacokinetic measurements FU plasma concentrations were determined at 0, 2.5, 5, 10, 15, 20, 30, 45, 60 min after drug administration. Plasma concentration-time curves were analysed according to one and two compartment, first order pharmacokinetic models. The models were fitted to the concentration-time data (weighting the values by 1/Y2) using nonlinear regression analysis software in GraphPad PRISM (San Diego, CA). The optimal model was chosen by calculating the Akaike Information Criterion [20]: AIC=Nrln(SSQ)+2p, where N is the number of samples, ln the natural logarithm, SSQ the sum of the f 2002 Blackwell Science Ltd Br J Clin Pharmacol, 54, 131–139
Fluorouracil kinetics and body composition
squared residues, and p the number of model parameters. The model yielding the lower AIC was chosen. The following pharmacokinetic parameters were then calculated: AUCð0,?Þ~C0 =k ð1 compartment modelÞ or A=l1 þ B=lz ð2 compartment modelÞ Clearance (CL)=Dose/AUC(0,?)
(r2). Slopes and intercepts of regression lines obtained in males and females were compared using the the GraphPad PRISM statistical software. Forward stepwise multiple regression analysis was carried out, using Statistica software (StatSoft Inc, Tulsa, OK), with CL or Vss as dependent variables, and BIA measures and sex as independent variables, in order to obtain the model most predictive of the pharmacokinetic parameters. In this analysis, both r2 and adjusted r2 were calculated.
Distribution volume at steady state (Vss)=Dose/C0 (1 compartment model) or
Results 2 2 2 1 +B/ z )/(A/ 1+B/ z)
Dose (A/l
l
l
l
(2 compartment model) Distribution volume of central compartment (Vc) =Dose/(A+B) (only for the 2 compartment model) Terminal half-life=0.693/k (1 compartment model) or 0.693/lz (2 compartment model) Initial half-life=0.693/l1 (only for the 2 compartment model) where A and B are y intercepts and l1 and lz are rate constants.
Statistical analysis Data were expressed as meants.d. Comparisons between mean values obtained in females and males were made using the Student’s t-test for unpaired data. 95% confidence intervals (CI) on differences were also calculated. The accepted significance level was P
