Lack of interaction between flucloxacillin and methotrexate in pa tien t s with rheumatoid arthritis

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1 Br J Clin Pharmacoll996; 41: Lack of interaction between flucloxacillin and methotrexate in pa tien t s with rheumatoid arthritis ARIANE L. HERRICK', DAVID M. GRENNAN', KERRY GRIFFEN', LEON AARONS2 & LARRY A. GIFFORD2 'University of Manchester Rheumatic Diseases Centre, Hope Hospital, and 'Pharmacy Department, University of Manchester, Manchester, U.K. The aim of the study was to examine the potential pharmacokinetic interaction between methotrexate and flucloxacillin. Ten rheumatoid arthritis patients participated in the interaction study. Subjects were allocated to either methotrexate alone (5-15 mg per week) or methotrexate plus flucloxacillin (500 mg four times a day 48 h prior to sampling) in a random order. There was a statistically, but not clinically, significant decrease in methotrexate AUC (1307 i-389 us 1212 f 394 pg I-' h) in the presence of flucloxacillin. C, and t,,, parameters for methotrexate were not significantly altered in the presence of flucloxacillin. Data from an additional 10 rheumatoid arthritis patients, starting on methotrexate, were added to the data from the placebo arm of the interaction study and a model dependent pharmacokinetic analysis was performed. The plasma concentration profiles were best described by a two-compartment model with a mean clearance of 11.9 (& 1.7) 1 h-l and an initial volume of distribution of 31.2 (& 2.6) 1. The pronounced intersubject variability in the pharmacokinetic parameters was not related to any of the available covariate information. Our findings suggest that no important clinical interaction occurs between flucloxacillin and methotrexate in patients with rheumatoid arthritis. Keywords methotrexate pharmacokinetics action rheumatoid arthritis NONMEM flucloxacillin-methotrexate inter- Introduction Low dose methotrexate (MTX) is now widely used as a second-line treatment for rheumatoid arthritis (RA) [ 11. Clinical effects and side effects have been shown to be dose related and MTX dosage should be individualized [2]. Differences in the pharmacokinetics of MTX between individuals is a potential source of variability in the dose-effect relationship and marked interindividual variability in MTX bioavailability has been noted [3]. Drug-drug interactions are another source of pharmacokinetic variability and several interaction studies involving MTX have been reported [4-61. Recently we observed the case of a 66 year old man with an 11 year history of RA, receiving weekly MTX (5 mg), who was treated with flucloxacillin (4 g i.v. four times a day, later switched to p.0.) for an infected ulcer of the left great toe. The patient became unwell 36 h after his weekly MTX developing fever and a cough. Subsequently he became breathless, his white cell count was 12.9 x lo9 I-l, he developed an eosinophilia, chest X-ray showed a bilateral alveolar shadowing and he became increasingly hypoxic. Antibiotics, including cotrimoxazole, were started, MTX discontinued and he made a gradual recovery. Although infection was initially suspected as the cause of his acute respiratory problem, no organism was ever isolated and a MTX pneumonitis was suspected. Impaired renal clearance of MTX by penicillins [7] has been demonstrated in animals. As low dose MTX is now widely used in the treatment of RA, and as RA patients on MTX are often prescribed penicillins for the treatment of infection, impaired clearance of MTX by penicillins could predispose this patient group to MTX toxicity. Consequently we undertook a study to investigate whether flucloxacillin might reduce the clearance Correspondence: Dr L. Aarons, Pharmacy Department, University of Manchester, Manchester MI3 9PL, U.K Blackwell Science Ltd 223

2 224 Ariane L. Herrick et al. of MTX in patients with RA. In addition to the interaction study, the pharmacokinetics of MTX were assessed in a further group of RA patients receiving MTX. Methods Patients and study design Ten RA patients (seven female, three male; median age 54 years, range years, median weight 64 kg, range kg), all of whom were being prescribed weekly oral MTX, were recruited into the study after signing informed consent. The study was approved by the Salford ethics committee. The median duration of MTX treatment was 2.5 years (range 3 months-8 years) and the median dose of MTX was 7.5 mg (range 5-15 mg). All ten patients were seropositive for rheumatoid factor and nine had erosive disease. In one patient plasma creatinine (134 pmol 1-I) was marginally elevated on one of the study days. Concomitant drug therapy was maintained during the study, with the exception of one subject whose dosage of prednisolone was reduced and another who was commenced on sulphasalazine. Pharmacokinetic profiles were obtained from each patient on two occasions 1 week apart (with the exception of one patient whose two profiles were 6 weeks apart). Patients were randomized to commence flucloxacillin 500 mg four times a day 48 h prior to either the first or second profile. Blood samples were taken on each occasion immediately pre-mtx and at 30 min and 1,2,4,8,12 and 24 h post-mtx. Flucloxacillin was discontinued after 72 h. In addition to the interaction study, MTX pharmacokinetic profiles were obtained from 10 patients with active RA commencing MTX (seven female, three male; median age 56 years, range years, median weight 65 kg, range kg). All but one patient had erosive disease and serum creatinine was within the normal range for all patients. Blood samples were obtained immediately before, and over 24 h after, the first dose of MTX (7.5 mg in nine patients; 5 mg in one patient). Assay Serum concentrations of MTX were measured by a fluorescence polarization immunoassay ( FPIA) with the Abbott TDX system (Abbott, USA). Control solutions were measured daily with each assay. The inter- and intraday coefficients of variation were less than 10% and the limit of detection was 0.01 pmol 1-'. The manufacturer claims that the cross-reactivity with 7-hydroxymethotrexate is less than 1 %. Data analysis The area under the concentration-time curve (AUC), up to the last measurable concentration, was calculated by the linear trapezoidal rule. C,,, and t,,, values were taken directly from the observed concentrations. A paired t-test was used to assess differences between the treatment phases. For the t-tests AUC and C,,, were dose normalized to a dose of 7.5 mg. A nonparametric confidence interval was calculated for t,,, [ 81. The concentration-time profiles were modelled using a mixed-effects approach implemented in the computer program NONMEM [9]. One- and two-compartment models with first order and zero order absorption were used to describe the pharmacokinetic model. The onecompartment model was parameterized in terms of clearance (CL) and volume of distribution (V), whereas the four parameters of the two-compartment model were CL, initial volume of distribution (V,) and the distributional rate constants, k,, and k2,. The volume of distribution at steady state (Ks) was calculated from these parameters as shown in Equation I. First-order absorption was characterized by the rate constant, ka, and zero-order absorption by the time of absorption, tabs, (where the input rate during absorption IS dose/t,b,). The pharmacostatistical model was given by the following equation:- where yij is the jth measurement on the ith subject, f is the model prediction, Pk is the kth parameter, 0: is the interindividual variance associated with the kth parameter (here assumed to be multiplicative) and IS: is the residual variance (again assumed to be multiplicative). The effect of flucloxacillin on the pharmacokinetics of MTX was assessed by comparing models which had different parameter values in the presence and absence of flucloxacillin. Tests of significance were performed on the difference in the objective function (-2 loglikelihood) between the fits which is approximately distributed as x2 with the number of degrees of freedom equal to the difference in the number of parameters between the two fits. In addition, the effect of the covariates age, weight, dose and gender was assessed by modelling the pharmacokinetic parameters as a function of the covariates and by inspection of plots of posterior estimates (essentially empirical Bayes estimates obtained from the population parameters and individual data) of the pharmacokinetic parameters as a function of the covariates. Results A summary of the analysis of AUC, C, and t,,,, for the interaction study is shown in Table 1 and mean plots of MTX plasma concentration in the absence and presence of flucloxacillin are shown in Figure 1. There Blackwell Science Ltd British Journal of Clinicd Phurmucology 41,

3 Flucloxacillin-methotrexate interaction 225 Table 1 Pharmacokinetic parameters for MTX in the absence and presence of flucloxacillin. AUC and C,,, been normalized to a dose of 7.5 mg. tmax is given as the median (range) - (mean+s.d.) have 95% CI for difference Pci ramrtrr -jucloxacillin t-jucloxacillin in mean values AUC (pg I -' h) 1307 k f394 [-186, -41 Cmax (w 1 '1 228 f f51 [-47, 251 tmax (h) 1.65 (0.83, 4.0) 1.02 (0.92, 2.0) [-0.99, L L w V 0 50 variance of 45% (expressed as a CV). The two half-lives associated with the two-compartment model were 1.1 and 6.4 h, respectively. The predicted mean profile (normalized to a dose of 7.5 mg) for the fit is shown in Figure 2. Based on the population parameters, posterior estimates of individual parameters were calculated and, for example, the individual posterior profile for subject 1 is shown in Figure 3. The posterior parameter estimates showed no obvious dependence on the available covariates: age, weight, gender or dose. 0 4 a Xrne (h) Figure 1 Mean plot of methotrexate concentrations (normalized to a 7.5 mg dose) in the absence (M) and presence (I I) of flucloxacillin. Data plotted at nominal times. Error bars are +s.e. means. was a statistically significant decrease (7.3%) in MTX AUC (P < 0.05) in the presence of flucloxacillin but,, C, and t,,, were unaltered. The results of the model dependent analysis confirmed the model independent analysis and a summary of these results is presented in Table 2. A two-compartment model gave a superior fit to the data and zero-order absorption was preferred to first-order. However, although the model gave an adequate fit to the data, the fit was not perfect and some underprediction was noted at later times (see Figure2). For the twocompartment model it was only possible to estimate interindividual variances for CL and V,. CL was significantly different in the absence (6.93f h-') compared with the presence (8.01-t h-') of flucloxacillin. There was weak evidence that k,, also differed between the treatments giving rise to V,, values of 130 f61 I in the absence and 44 & 10 1 in the presence of flucloxacillin, although this difference did not reach significance. The data from the interaction study in the absence of flucloxacillin was combined with the additional profiles to give data on 20 subjects. The zero order twocompartment model was fitted to this data and the results of this analysis are shown in Table 3. With the additional data it was possible to calculate interindividual variances for CL, V,, kz1 and tabs. There is some discrepancy between the parameter estimates between Tables 2 and 3 which is due to the sensitivity of the mean estimates to the number of subjects when that number is relatively small. From these estimates Vs, can be calculated to be , with an interindividual Discussion Penicillins have been reported to reduce the renal clearance of MTX in man [lo] and in laboratory animals [ 71. It has been suggested that penicillins and MTX share a similar carrier protein in the renal tubule from studies using a rabbit slice model [ll]. However, in the present investigation a lower AUC was observed for MTX in the presence of flucloxacillin. In addition to our observation in one patient of the development of acute respiratory symptoms, consistent with a MTX pneumonitis, following treatment with flucloxacillin there exist a number of anecdotal reports from which an association between penicillins and MTX toxicity might be inferred. In a report of five patients on MTX who developed neutropenia (three had psoriasis, two RA) two had penicillins prior to hospitalisation and two others shortly after [12]. Three of the four patients receiving penicillins died. The authors hypothesised that the penicillin antibiotics may have interfered with MTX excretion. Engelbrecht et al. [ 131 reported a patient with RA on low dose MTX who experienced a rapid deterioration in respiratory function following prescription of amoxycillin. While these isolated case reports do not allow any conclusion to be drawn regarding the possibility of an interaction between penicillins and MTX, nonetheless they do highlight the clinical point that patients on MTX, in whom infection is suspected, are often treated with penicillins. Consequently we undertook the present study in which we found, despite the slightly lower MTX AUC in the presence of flucloxacillin, that in our group of patients no important interaction occurred between flucloxacillin and MTX. Flucloxacillin should therefore not potentiate MTX toxicity in this patient group. Nevertheless, as the study was only pharmacokinetic in nature, an effect of flucloxacillin on the efficacy and safety of MTX through other mechanisms cannot be excluded Blackwell Science Ltd British Journal of Clinical Pharmacology 41,

4 226 Ariune L. Herrick et al. Table 2 Results of model dependent analysis of MTX in the absence and presence of flucloxacillin 1 cmpt FO 2 cmpt FO Model' Purameter estimates' Objrctive function.' CL split between treatments CL and k,, split between treatments (CL,, kzl,,-absent CL,, k,,,,-present) 0: (CL,-absent Vl (1) CL,-present ) kl, (h-l) k2l (h-l) tabs ( h, 4 L 4, d CL, (1 h-l) Vl (1) kl' (h-') k21.a (h-') k21.p (h-') labs (h) 4 L (41 0% x lo-* (0.46) (3.0) (0.55) (0.0136) (2.44 x lo-' ) (0.56) (0.025) (0.80) (1.22) (0.094) (0.0188) (0.014) (0.132) (0.0221) (1.45) (2.91) (0.0319) (0.0352) (0.145) (0.123) (0.045) (0.027) (1.19) ( 1.20) (3.6) (0.0099) (0.0420) (0.15) (0.181) (0.033) (0.86) (2.24) (4.3) (0.032) (0.0132) (0.032) (0,119) (0.355) (0.052) ' FO ~ first order absorption; ZO - zero order absorption; 1 and 2 cmpt - one- and two-compartment models. 'Values in parentheses are s.e. means. The square root of the variance terms are approximately equal to coefficients of variation of either the associated parameter or of the residual variability. "A change in the objective function of for one extra parameter would be considered to be a significant improvement in the fit based on a x2 statistic (P<O.Ol). The investigation has also allowed a characterization of the pharmacokinetics of MTX in rheumatoid arthritis patients. The terminal half-life of MTX in RA patients has been reported to be relatively short in studies conducted over 24 h [ 141, in keeping with our findings. However Seideman et al. [ 151 found a terminal half-life of 49 h after sampling for 7 days. However in the latter study the apparent oral clearance, h-', was similar to the value found in the present study indicating that the long terminal half-life does not contribute appreci- ably to the accumulation of the drug in plasma. Significant interindividual variability, which could not be attributed to any patient characteristic, was seen in the pharmacokinetic parameters. However subject numbers were small and a larger study might reveal the cause of some of this variability. Although a doseresponse relationship has been described for MTX in RA patients [2] it is not currently known how much of the variability in the dose-response relationship is pharmacokinetic in origin Blackwell Science Ltd British Journal of Clinicul Pharmacology 41,

5 ~ loo0 1 Flucloxacillin-methotrexate interaction 227 The financial support of the North West Regional Health Authority is gratefully acknowledged. References 1L- ' I I I 1 % I lime (h) Figure 2 Plot of methotrexate concentrations and population profile (normalized to a 7.5 mg dose). Table 3 Results of the model dependent analysis (2 cmpt ZO) of the combined MTX data Parameter Estimate (s.e. mean j Objective function Iooo r (1.72) (4.0) (0.042) (0.039) (0.14) (0.539) (0.083) (0.077) (1.67) (2.6) (0.028) (0.019) (0.10) (0.85) (0.0302) (0.414) (0.079) (0.0198) Bannwarth B, Labat L, Moride Y, Schaeverbeke T. Methotrexate in rheumatoid arthritis. An update. Drugs 1994; 47: Seideman P. Methotrexate-the relationship between dose and clinical effect. Br J Rheumatol 1993; 32: Lebbe C, Beyeler Ch, Gerber NJ, Reichen J. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis. Ann Rheum Dis 1994; 53: Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC. The effects of salicylate, ibuprofen and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol 1992; 42: Lafforgue P, Monjanel-Mouterde S, Durand A, Catalin J, Acquaviva PC. Is there an interaction between low doses of corticosteroids and methotrexate in patients with rheumatoid arthritis? A pharmacokinetic study in 33 patients. J Rheumatol 1993; Anaya J-M, Fabre D, Bressolle F, et al. Effect of etodolac on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol 1994; 21: Williams WM, Chen TS, Huang KC. Effects of penicillin on the renal tubular secretion of methotrexate in the monkey. Cancer Res 1984; Gardner MJ, Altman DG. Statistics with Confidence. The British Medical Journal, London, 1989, pp Beal SL, Sheiner LB. The NONMEM system. Am Statistician 1980; Bloom EJ, Ignoffo RJ, Reis CA, Cadman E. Delayed clearance of methotrexate associated with antibiotics and anti-inflammatory agents. Clin Res 1986; 34: 560A. 11 Neirenberg DW. Drug inhibition of penicillin tubular secretion: concordance between in vitro and clinical findings. J Pharmacol Exp Ther 1987; Mayall B, Poggi G, Parkin JD. Neutropenia due to lowdose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal. Med J Aust 1991; 155: Engelbrecht JA, Calhoon SL, Scherrer JJ. Methotrexate pneumonitis after low-dose therapy for rheumatoid arthritis. Arthritis Rheum 1983; 26: Kozloski GD, De Vito JM, Kisicki JC, Johnson JB. The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers. Arthritis Rheum 1992; Seideman P, Beck 0, Eksborg S, Wennberg M. The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis. Br J Clin Pharmacol 1993; 35: (Received 17 July 1995, accepted 27 October 1995) 1 L ~- 0 1 I 1 I Time (h) Figure 3 Population (-) and posterior (---) fits for subject Blackwell Science Ltd British Journal of Clinical Pharmacology 41,