ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1987, 0066-4804/87/071140-03$02.

00/0 Copyright 1987, American Society for Microbiology

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Vol. 31, No. 7

Pharmacokinetics of a Single Dose of Rimantadine Young Adults and Children

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EDWIN L. ANDERSON,l* LEE P. VAN VORIS,1t JULIE BARTRAM,W HOWARD E. HOFFMAN,2 AND ROBERT B. BELSHE1 Department of Medicine, Marshall University School of Medicine, Huntington, West Virginia 25701,1 and Pharmaceuticals-Biomedical Products Department, Stine-Haskel Laboratory, E. I. Du Pont de Nemours & Company, Newark, Delaware 197142
Received 28 January 1987/Accepted 20 April 1987

Single doses of rimantadine were given to children and young adults to evaluate the safety and pharmnacokinetics of this antiviral compound. The half-life of rimantadine in young adults was 27.7 + 4.9 h for tablets and 27.8 + 8.0 h for syrup preparations. A total of 10 children, 5 to 8 years old, received a syrup preparation of rimantadine. The half-life of rimantadine in children was 24.8 9.4 h. A single dose of rimantadine was well tolerated in young adults and children.

To study the pharmacokinetics of rimantadine in young adults and young children, single doses of oral rimantadine were given to healthy representatives of these populations. The purpose of the study with young adults was to compare the pharmacokinetics of rimantadine in tablet form (100-mg tablets) and in syrup form (10 mg/ml) in normal volunteers. The rimantadine was given as a single dose with appropriate plasma and urine studies. A randomized crossover study comparing the pharmacokinetics of single-dose oral rimantadine in syrup and tablet forms was completed with 24 adults. The pharmacokinetics of rimantadine was then studied in 10 young children. This report summarizes these two studies. Adult male volunteer subjects were recruited from the third- and fourth-year classes of the Marshall University

ized to receive either tablet or syrup for the Initial dosing. Plasmna specimens were subsequently drawn at 30 min and at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h. In addition, a zero-time urine specimen was obtained, and subsequent Urine specimens were collected at the following intervals: 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 h after rimantadine was administered. Seven days after the initial rimantadine preparation was administered, the alternate crossover preparation was administered, and plasma and urine samples were collected as outlined above. Pediatric subjects were recruited as follows. Parents of children aged 4 to 8 years, inclusive, were contacted, and a brief description of the study was presented. Children and parents were asked to visit the offices of the investigators to further discuss the protocol if they expressed interest in the

TABLE 1. Pharmacokinetic parameters in young adults receiving rimantadine tablets or syrupa

rmantadine
Tablet Syrup

Cmax (ng/ml)

Tmax (h)

310 99 319 103

4.3 2.3 3.2 2.0

AUC (ngh/ml) 11,917 4,421

t1/2 (h)
27.7 4.9 27.8 8.0

t1/2 abs (h)

CL (ml/min

Varea (liters) 727 201 768 225

3.9 1.3 4.3 1.7

a Cmax, Maximum concentration; Tm., time of maximum concentration; AUC, area under the curve for concentration in plasma versus time; '1/2, half-life; abs, absorption half-life; CL, total drug clearance; Varea, apparent volume of distribution. Values are means SD.

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School of Medicine and from the Internal Medicine and Family Practice house staff of the Marshall University Affiliated Hospitals residency training program. Volunteers provided their medical histories and underwent physical examinations. Screening laboratory studies included a complete blood count and differential, routine urinalysis, determination of T4 in serum, syphilis serology, and a complete chemistry profile, including studies of electrolytes, renal function, and liver function. Volunteers had fasted for 12 h before beginning the study. After the initial zero-hour plasma specimen was obtained, 200 mg of rimantadine was administered to each volunteer. Volunteers were random* Corresponding author. t Present address: Hamot Medical Center, Erie, PA 16550.

study. The study was explained in detail to parehts and children. Parents signed a detailed informed consent form. Children over the age of 6 years also signed an informed consent form which contained pictographs and simple explanations of the study and the reasons for performing the study. A medical history was obtained, and a physical examination and laboratory studies were done before administration of the drug. Base-line laboratory studies included a complete blood count and determinations of liver enzymes and serum creatinine. Each volunteer had a normal physical examination and normal laboratory studies and was free of acute or chronic illness at the time of study. Rimantadine was administered in syrup form at a dose of 6.6 mg/kg of body weight. Plasma was obtained before administration of the drug and then at 6, 24, 48, and 72 h after
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10

20

30

40

SO HOURS

60

70

80

90

100

FIG. 1. Concentrations of rimantadine hydrochloride in plasma from human subjects. Means of all tablet data are compared with means of all syrup data. A, Tablet; 0, syrup. Bars represent 1 standard deviation.

administration of rimantadine. Urine was colle,cted for 24 h beginning immediately after administration of the oral dose. Rimantadine concentrations were measured in plasma and urine by electron captu,re gas chromatography assays as previously described (5). The RS-1 program (BBN Research Systems, Cambridge, Mass.) was used to determine pharmacokinetic parameters. The maximum concentration found and the hours postdose of the appearance of the maximum concentration were assumed to be 6 h, because of the limited number of plasma specimens that can be obtained from young volunteers and because of the data obtained with adult volunteers. The area under the curve for concentration in plasma versus time was determined by a computer program which used the method of trapezoids. The half-life (t1/2) was determined from the elimination rate constant (kel) (i.e., ti/2 = 0.693/kel). The elimination rate constant was derived from the linear regression slope of the terminal log linear portion of the curve for concentration in plasma versus time. The total drug clearance and volume of distribution were calculated according to standard definitions. Parametric and
TABLE 2. Concentration of rimantadine in plasma from children after a single oral dose Concn (ng/ml) at ha Subject no.
6 24 48

72

1 2 3
4 5 6 7 8 9 10

606 756 446 500 816 730 752 988 450 526 SD 657 180

316 420 170 308 424 252 254 406 208 246 300 86

<5 306 70 216 218 124 112 236 128 202

<5 218 10
130 160 <5 30 106 <5

138
79 77

Mean
a

At 0 h, all concentrations were <5 ng/ml of plasma.

nonparametric statistical tests for paired samples were used as indicated. A total of 24 adults received 200 mg of rimantadine in tablet form, and 19 adults received 200 mg of syrup preparation; 18 adults participated in the crossover study and received both preparations of rimantadine. One volunteer was withdrawn from the study after suffering a headache, blurred vision, and brief ringing in his ears after syrup ingestion. His headache responded to acetaminophen, and his other symptoms cleared rapidly. It was not clear whether his symptoms were related to drug ingestion. He did not crossover into the tablet phase of the study. There were no clinically significant reactions among the other volunteers. The pharmacokinetic data for adult subjects receiving tablets or syrup are summarized in Table 1. No statistically significant differences in pharmacokinetic parameters were found between the two drug preparations. The concentrations of rimantadine in plasma from adult volunteers after ingestion of tablets or syrup are compared in Fig. 1. At all times, from 0.5 through 96 h, the mean concentrations of rimantadine in plasma for volunteers receiving tablets or syrup were within 1 standard deviation for each preparation. Very little rimantadine appeared in the urine. Less than 1% of ingested drug was excreted. Nine boys and one girl participated in the study of rimantadine in young children. They ranged from 5 to 8 years old. No child had a significant clinical reaction to the single dose of rimantadine. Concentrations of rimantadine in plasma after the single oral dose are shown in Table 2. The highest concentrations occurred at 6 h after ingestion and ranged from 446 to 988 ng/ml (mean + standard deviation [SD], 657 + 180). After 24 h, samples of plasma from 10 children had detectable concentrations of rimantadine which ranged from 170 to 424 ng/ml (mean SD, 300 + 86). After 48 h, 9 of 10 volunteers had detectable rimantadine in plasma (range, 70 to 306 ng/ml). After 72 h, 7 of 10 volunteers had concentrations of rimantadine in plasma ranging from 10 to 218 ng/ml. Urine collection over 24 h revealed that less than 2% of the drug was excreted in the urine in the first 24 h, indicating that a single dose of drug is largely metabolized.

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ANTIMICROB. AGENTS CHEMOTHER.

TABLE 3. Pharmacokinetic parameters for rimantadine in pediatric subjects'"

Tm.. (h)
5.4 5.0 5.2 6.3 5.1 6.2 5.7 6.1 6.0 5.9

AUC (ng.h/ml)

t1/2 (h)

CL (ml/min per kg)

Varea (liters)

1 2 3 4 5 6 7 8 9 10
Mean + SD

606 756 446 500 816 730 752 988 450 526

14,003 28,062 10,790 19,166 26,039 17,003 17,444 27,298 12,840 17,994

19.8 38.5 12.6 34.7 28.9 16.7 14.7 21.7 23.0 36.5 24.8 9.4

7.8 3.9 10.2 5.8 4.2 3.9 8.3 4.0 8.6 6.1
6.3 2.3

347 287 329 329 250 242 165 222 339 377
289 67

657 180

5.7 0.5

19,064 6,131

aC6 h. Peak cpncentration of drug in plasma at 6 h postdose. For other abbreviations, see Table 1, footnote a.

Pharmacokinetic data for the children are shown in Table 3. In children, the elimination half-life ranged from 12.6 to 38.5 h (mean SD, 24.8 9.4). This time is not significantly different from the mean elimination half-life observed in adults given syrup preparation (P = 0.37). Clearance of the drug ranged from 3.9 to 10.2 ml/min per kg (mean SD, 6.3 2.3). This result was significantly different from that with the adult subjects (P = 0.01). Studies have been done on the pharmnacokinetics and safety of rimantadine in elderly and young adults (2-4), but no results had been reported for young children. Hayden et al. (4) reported the elimination half-life of rimantadine (given as tablets) in 6 young adults to be 36.5 17.3 h and in 10 elderly adults to be 36.5 14.5 h. We performed statistical comparisons of these results with our results. The elimination half-life measured among the 23 young adults in our study (mean, 27.7 4.9 h) was not significantly shorter than results reported by Hayden et al. (4) among either his young (36.5 17.3 h; P = 0.49) or elderly (36.5 + 14.5 h; P = 0.17)

The pharmacokinetic parameters suggest that once-daily administration of rimantadine would be suitable for children or adults.
We acknowledge the contribution of Barbara Mossello, who performed the rimantadine assays. This work was supported in part by a grant from E. I. Du Pont.
LITERATURE CITED 1. Glezen W. P., A. Paredes, and L. H. Taber. 1980. Influenza A in children. Relationship to other respiratory agents. J. Am. Med. Assoc. 243:1345-1349. 2. Hayden F. (;., J. M. Gwaltney, Jr., R. L. Van de Castle, K. F. Adams, and B. Giordani. 1981. Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Antimicrob. Agents Chemother, 19:226-233. 3. Hayden, F. G., H. E. Hoffman, and D. A. Spyker. 1983. Differences in side effects of amantadine hydrochloride and rimantadine hydrochloride relate to differences in pharmacokinetics. Antimicrob. Agents Chemother. 23:458-464. 4. Hayden, F. G., A. Minocha, D. A. Spyker, and H. E. Hoffman. 1985. Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults. Antimicrob. Agents Chemother. 28:216-221. 5. Mullooly, J. P., and W. H. Barker. 1982. Impact of type A influenza on children: a retrospective study. Am. J. Public Health 72:1008-1016.

subjects. Because schoolchildren may be responsible for the spread of significant amounts of influenza A and since children commonly become seriously ill with influenza, this population is one that may benefit significantly from taking rimantadine either therapeutically or prophylactically (1, 5).