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 hydrochlo- ride 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 deter- mined 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).