Effect of Cimetidine on the Disposition of Rimantadine in Healthy Subjects ALICE A

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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1989, p. 820-823 Vol. 33, No. 6 0066-4804/89/060820-04$02.00/0 Copyright C 1989, American Society for Microbiology

Effect of Cimetidine on the Disposition of Rimantadine in Healthy Subjects ALICE A. HOLAZO,* NADIA CHOMA, SHARON Y. BROWN, LUEN F. LEE, AND ROBERT J. WILLS Department of Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 Received 28 December 1988/Accepted 1 March 1989

Twenty-three healthy male and female subjects received single 100-mg oral doses of rimantadine hydrochloride on two occasions in an open-label, sequential design with a 6-day washout between doses. The first dose of rimantadine was administered alone, and the second dose was administered concomitantly with cimetidine (300 mg four times a day for 6 days). Blood and urine samples were collected, and rimantadine concentrations were determined by a gas-chromatographic-mass-spectrometric method. There were no changes in the rate of absorption and the renal clearance of rimantadine when it was administered with cimetidine. Both parametric and nonparametric tests showed significant differences in the area under the concentration-time curve, apparent total clearance, and elimination rate constant between the treatments (P < 0.01). The apparent total clearance was reduced by 18%, resulting in higher values for the area under the concentration-time curve in the presence of cimetidine. However, the wide therapeutic index of rimantadine renders these changes of little, if any, clinical consequence.

Rimantadine (oc-methyl-l-adamantanemethylamine hydro- For treatment A, a single 100-mg tablet of rimantadine chloride), an analog of amantadine with equipotent antiviral hydrochloride was administered with 240 ml of water 1 h activity (5, 6), is being evaluated for prophylaxis and treat- after a standard breakfast on the morning of day 1. For ment against influenza A viral infections (1, 2, 8-10, 13, 17). treatment B, a single 100-mg tablet of rimantadine hydro- Rimantadine is extensively metabolized by the liver, and chloride was administered with 240 ml of water 1 h after the renal excretion of the parent drug and its metabolites is the first dose of a 300-mg four-times-a-day regimen of cimetidine major pathway of elimination (4, 14-16). Drugs which affect on the morning of day 7. Each subject received a single the hepatic microsomal enzyme systems have the potential 300-mg tablet of cimetidine four times a day with meals and for altering the metabolism of rimantadine, since the major at bedtime. Thereafter, each subject took home the required pathway is hydroxylation. The histamine H2 receptor antag- number of tablets and continued the cimetidine regimen for onist cimetidine is known to have an inhibitory effect on the next 5 days. Cimetidine is an established alternate hepatic oxidative drug-metabolizing enzymes (12). Since substrate for the cytochrome P-450 enzyme system. Enzyme rimantadine may be prescribed for patients taking cimeti- kinetics dictate that competition for the enzyme system will dine, the potential metabolic interaction between these two occur as long as the alternate substrate (cimetidine) is drugs provided the rationale for investigating the effect of present. By way of clinical example, Feely et al. (3) showed cimetidine on the disposition of rimantadine. The aim of the that administration of cimetidine 1 h before administration of present study was to compare the disposition of rimantadine the test dose of antipyrine resulted in the same reduction of after single 100-mg oral doses of rimantadine hydrochloride antipyrine clearance as administration of cimetidine 24 h before and during cimetidine treatment in healthy subjects. before antipyrine administration, as long as cimetidine ad- MATERIALS AND METHODS ministration was continued throughout the test. Therefore, it is only necessary to administer cimetidine over the entire Twenty-three healthy subjects (20 male and 3 female), time course of the test substrate (rimantadine). ranging in age from 22 to 45 years and ranging in weight from The subjects remained seated or ambulatory for at least 4 57 to 89 kg, participated in this study after giving their h after administration of the rimantadine dose. Lunch was written, informed consent. Only females of non-child-bear- served after collection of the 4-h blood sample, and dinner ing potential were admitted into the study. The subjects were was served 6 h later. Subjects remained under observation in good general health as determined by base-line history, for 24 h after each dose of rimantadine. During this time, any physical examination, hematologic examination, urinalysis, adverse experiences were recorded on the case report form. and determination of serum chemistries. The use of alcohol Blood pressure and heart rate were measured 2, 12, and 24 h and over-the-counter drugs was excluded for 72 h prior to after each rimantadine dose, while the subjects were seated. dosing and throughout the course of the study. The protocol The subjects were released from the study unit after collec- was approved by the Institutional Review Board of the tion of the 24-h blood sample, and they returned to the unit Newark Beth Israel Medical Center. for collection of the remaining samples. Laboratory deter- This study was conducted in an open-label, single-dose, minations were repeated before treatment B. The vital-sign sequential design with a minimum 6-day washout between monitoring and laboratory tests performed for entry into the doses. The subjects reported to the study unit 12 h prior to study were repeated within 1 week of completion of the drug administration on days 1 and 7. The next morning each study. subject received treatment A (rimantadine alone) on day 1 Blood samples (14 ml) were collected into heparinized and treatment B (rimantadine plus cimetidine) on day 7. tubes before drug administration (0 h) on day 1, and then 7-ml samples were collected at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, * Corresponding author. 72, 96, 120, and 144 h after administration of rimantadine on 820 VOL. 33, 1989 EFFECT OF CIMETIDINE ON RIMANTADINE DISPOSITION 821 days 1 and 7. Urine specimens were obtained before drug 100- administration (-12 to 0 h) on day 1 and at the following intervals after administration of rimantadine on days 1 and 7: E ol 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, 48 to 72, 72 1-1 to 96, 96 to 120, and 120 to 144 h. Plasma and urine samples Cc C were stored at -17°C until assayed. The concentrations of 0 unchanged rimantadine in plasma and urine were determined '-0 (DL by a gas-chromatographic-mass-spectrometric assay (4). 0 --l The assay involves selective ion monitoring, methane nega- UC C), tive-ion chemical ionization, and stable-isotope dilution. a0 10- --l Sensitivity to methane negative-ion chemical ionization is --l CLc -0 effected by derivatization of rimantadine with pentafluo- 0 0 10 robenzoyl chloride. For plasma, the mean coefficients of 0 variation for interassay and intra-assay precision were 3.1 C and 4.9%, respectively, over a calibration range of 5 to 500 0 ng/ml. For urine, the mean coefficients of variation for c interassay and intra-assay precision were 2.4 and 6.4%, 0 respectively, over a calibration range of 25 to 2,500 ng/ml. Pharmacokinetic parameters of rimantadine were determined from the concentration-time data for plasma and the -4rn I 1I urinary excretion data. The maximum concentration (Cmax) 0 12 24 36 48 00 72 84 96 and the time of maximum concentration (Tmax) were read Time (hours) directly from the concentration-time data for plasma. The FIG. 1. Profiles of mean rimantadine concentration in plasma apparent elimination rate constant (t) was calculated by versus time following single 100-mg oral doses of rimantadine least-squares regression analysis on the terminal log-linear hydrochloride administered alone (0) and concomitantly with ci- phase of the concentration-time curve for plasma. The metidine (0) to healthy subjects. terminal half-life (t4/2,) was calculated by dividing In 2 by P. The areas under the concentration-time curve for plasma from time zero to the time of the last measurable plasma tantly with cimetidine than when it was administered alone concentration point (AUC,) were calculated by linear trape- (Fig. 1). Cmax ranged from 50 to 113 ng/ml at a Tmax of 2 to zoidal summation. Extrapolation to time infinity (AUC) was 6 h with rimantadine alone and from 57 to 169 ng/ml at 2 to determined by dividing the last measurable point for concen- 8 h with cimetidine. There were no statistically significant tration in plasma by , and adding the result to the corre- differences between the two treatments in these parameters. sponding AUC,. A significant difference, however, was detected in the elim- The apparent total clearance (CL/F) of rimantadine and ination rate constant by both the paired t test and the signed the apparent volume of distribution (V/F), where F is the rank test (Table 1). The harmonic mean elimination half-lives fraction of the oral dose reaching the systemic circulation, were 24.9 h without cimetidine and 29.1 h with cimetidine. were calculated = = The mean apparent total clearance of unchanged rimanta- by CL/F dose/AUC and V/F dose/ dine was < reduced (AUC x P). The concentration of unchanged drug in urine (CL/F) significantly (P 0.01) during and the total urine output from times t1 to t2 were used to calculate the excretion of rimantadine from the urine during 1000- each collection interval (X",-2) and the overall excretion of drug during the entire collection period (XI0144). The renal clearance (CLR) was calculated by CLR = XU0144/AUC, and the apparent nonrenal clearance (CLNR/F) was calculated as the difference between CL/F and CLR. The parameters Cmax, Tmax, AUC, P, CL/F, and CLR were subjected to statistical analysis. Each pharmacokinetic parameter was analyzed separately. For each parameter and subject, the difference between the values when rimantadine was administered alone and when it was given concomitantly with cimetidine was calculated. These differences were subjected to the paired t test and the nonparametric signed rank test, with P > 0.05 being taken as not significant. 0~~~~~~~~~~

RESULTS Mean concentration-time profiles for rimantadine in plasma following the administration of rimantadine alone and with cimetidine are in concomitantly presented Fig. 1, 10 and profiles of mean excretion rate in urine versus time are . 300 12 24 48 0 72 84 8 108 120 132 shown in Fig. 2. The mean rimantadine pharmacokinetic Time (hours) parameters following both treatments, together with the FIG. 2. Profiles of mean excretion rate of unchanged rimantadine results of the statistical analysis, are presented in Table 1. in urine versus time following single 100-mg oral doses of rimanta- Mean rimantadine concentrations in plasma were consis- dine hydrochloride administered alone (-) and concomitantly with tently higher when rimantadine was administered concomi- cimetidine (O) to healthy subjects. 822 HOLAZO ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1. Rimantadine pharmacokinetic parameters after single 100-mg oral doses in the absence and presence of cimetidine Rimantadine alone Rimantadine + cimetidine Parameter P Mean ± %CV" Range Mean ± %CV" Range Cmax (ng/ml) 79 ± 20% 50-113 86 ± 30% 57-169 NSb Tmax (h) 3.4 ± 35% 26 4.0 ± 44% 2-8 NS AUC (ng. h/mi) 2,755 ± 40% 1,197-4,968 3,313 ± 41% 1,666-6,665 <0.01 P (h'-) 0.0278 ± 32% 0.0138-0.0485 0.0238 ± 31% 0.0124-0.0398 <0.01 t1/2p (h) 24.9' 14.3-50.2 29.1c 17.4-55.9 V/F (liters/kg) 21 ± 19% 13-28 20 ± 15% 13-28 CL/F (ml/min per kg) 9.64 ± 39% 4.47-19.07 7.95 ± 35% 3.33-13.55 <0.01 CLR (ml/min per kg) 1.16 ± 44%" 0.32-2.50 1.02 ± 57%e 0.19-2.58 NS CLNR/F (ml/min per kg) 8.63 ± 41% 4.14-17.71 7.03 ± 37% 3.14-12.82 % Excreted unchanged in urine 12.3 ± 37%d 6.7-23.6 12.9 + 42%e 5.0-24.9 (0 to 144 h) a CV, Coefficient of variation. b NS, Not significant at 5% level of significance. c Harmonic mean. d n = 21 (excluding subjects 13 and 20). en = 21 (excluding subjects 13 and 18).

cimetidine treatment, from 9.64 to 7.95 ml/min per kg, and metabolic transformations (e.g., hydroxylation and dealkyl- consequently, the mean AUC was significantly (P < 0.01) ation). Any inhibition of the oxidative pathway would be increased, from 2,755 to 3,313 ng. h/ml. The values for the expected to result in a reduction in clearance and an increase apparent volume of distribution (V/F) ranged from 13 to 28 in drug concentrations in the circulation, as was found in the liters/kg for both treatments. present study. The renal clearance (CLR) of unchanged drug ranged from A recent review (12) of pharmacokinetic interactions of 0.32 to 2.50 ml/min per kg without cimetidine and from 0.19 cimetidine stated that the degree of inhibition of drug me- to 2.58 ml/min per kg with cimetidine. Statistical analysis tabolism by cimetidine at a daily dose between 800 and 1,600 showed no significant differences between treatments. The mg would be in the range of 30 to 40%. The decrease in absence of an effect of cimetidine on the CLR is also shown apparent clearance of 18% reported here suggests that the in the percentage of the dose recovered unchanged in the inhibition of rimantadine metabolism is less than the average urine over 144 h (12.3% without cimetidine; 12.9% with seen with other drugs for a 1,200-mg/day dose of cimetidine. cimetidine) and in the excretion rate in urine at various time More important than the degree of inhibition is the clinical intervals (Fig. 2). consequence. Unfortunately, pharmacodynamic measurements of rimantadine are not useful in the absence of DISCUSSION influenza A infection, since these measurements largely involve improvement in influenza-related symptomatology The values of the pharmacokinetic parameters for riman- such as a decrease in body temperature. However, there is tadine in the absence of cimetidine dosing were consistent evidence that the therapeutic index for rimantadine is wide. with those obtained in previous single- and multiple-dose Patriarca et al. (8) reported no correlations between adverse studies in healthy subjects (14-16). Unlike the procedure in experiences and rimantadine concentrations in serum which other interaction studies with cimetidine, in the present ranged from 634 to 2,600 ng/ml 3 to 4 h after the last dose of study the subjects were not pretreated with cimetidine prior a 100-mg-twice-daily 10-day regimen. Similarly, there were to administration of the rimantadine dose. This would be no correlations between rimantadine concentrations in se- deemed necessary only if there was interest in evaluating a rum in excess of 1,000 ng/ml and adverse events in studies potential pH-dependent effect on absorption. This was con- conducted by the Rochester group (R. Betts and R. Dolin, sidered unlikely for rimantadine, since rimantadine is a weak personal communication). Following a prophylactic or ther- base (PKa 10.4) and the in vitro dissolution profile was apeutic regimen of 100 mg twice daily, maximum concentra- shown to be pH independent over a pH range of 1.2 to 7.0 tions of rimantadine in plasma at steady state range from 240 (K. Iqbal, personal communication). Under the acute con- to 570 ng/ml (16). Therefore, a 15 to 20% increase in ditions of this study, no statistically significant changes were rimantadine concentrations in plasma is not expected to be observed in the Cmax and Tmax values, indicating that cimet- of any clinical consequence. idine had no effect on the rate of absorption of rimantadine. In conclusion, the absorption and renal clearance of Concomitant administration of cimetidine resulted in a rimantadine were not altered by the presence of cimetidine. statistically significant change in the apparent clearance of The apparent total clearance was reduced by 18%, resulting rimantadine. The mean apparent total clearance (CL/F) was in higher AUC values in the presence of cimetidine. How- reduced by approximately 18% during cimetidine treatment. ever, the wide therapeutic index renders this change of little, Since CLR remained unchanged and absorption was unaf- if any, clinical consequence. fected, the reduction in CL/F could be attributed mainly to nonrenal mechanisms. Rimantadine is biotransformed pri- marily by hepatic microsomal oxidation to its hydroxylated metabolites, with only 8 to 16% of the dose being excreted ACKNOWLEDGMENTS unchanged in the urine (4, 14). Since cimetidine binds We acknowledge Roy Bloch for his technical assistance and reversibly to the microsomal cytochrome P-450 enzyme Patricia Seymore for her secretarial assistance in the preparation of system (7, 11), it is an effective inhibitor of phase I drug the manuscript. VOL. 33, 1989 EFFECT OF CIMETIDINE ON RIMANTADINE DISPOSITION 823

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