Pharmacokinetics of Promethazine Hydrochloride After Administration of Rectal Suppositories and Oral Syrup to Healthy Subjects

Laura C. Strenkoski-Nix, James Ermer, Sheryl Decleene, William Cevallos, and Philip R. Mayer

Disclosures

Am J Health Syst Pharm. 2000;57(16) 

In This Article

Results

Thirty-seven subjects were enrolled, and 36 of them completed the study. After enrollment and completion of study period 1 (treatment D, 50 mg [10 mL] of promethazine oral syrup), one subject was withdrawn from the study because of violation of study protocol. There were 18 female and 18 male subjects; 3 were black, 13 were Hispanic, and 20 were white. The mean ± S.D. age was 30 ± 8.2 years, and the mean ± S.D. weight was 69 ± 11 kg.

Figure 1 shows individual and mean plasma promethazine concentration- versus-time curves for all four treatments. For direct comparison, mean plasma promethazine concentrations for the four treatments are shown in Figure 2. More than 90% of the subjects had measurable plasma promethazine concentrations at 48 hours. In addition, a number of subjects in each treatment group had measurable promethazine concentrations at time zero (carry-over from the previous dose), ranging from 0.05 to 1.3 ng/mL. The mean percent AUC0- accounted for by predose concentrations was 2% for treatments A, B, and C and 0.3% for treatment D.

Promethazine concentration-versus-time curves for two 12.5-mg promethazine suppositories (A), one 25-mg promethazine suppository (B), one 50-mg promethazine suppository (C), and 50 mg (10 mL) of promethazine oral syrup (D). Dashed lines represent individual curves, and solid lines represent mean curves.

Mean promethazine concentration-versus-time curves for two 12.5-mg promethazine suppositories (diamonds), one 25-mg promethazine suppository (open circles), one 50-mg promethazine suppository (squares), and 50 mg (10 mL) of promethazine oral syrup (closed circles).

Pharmacokinetic findings for the treatments are summarized in Table 1. The absorption of promethazine was quite variable for all four formulations, although there was less variability with the syrup. On average, promethazine was absorbed more rapidly and reached a higher Cmax after oral administration than after rectal administration. After the 50- mg oral dose, Cmax ranged from 6.4 to 54 ng/mL. Cmax was significantly lower for the 50-mg suppository (range, 1.0-34 ng/mL) than for the oral syrup. After syrup administration, tmaxoccurred significantly earlier (mean, 4.4 hours) than after suppository administration (mean, 6.7-8.6 hours). There were no significant differences between two 12.5-mg suppositories and one 25-mg suppository with respect to AUC. AUC0- was comparable between the 50-mg suppository and the syrup. Elimination profiles were similar for the four treatments (mean t1/2, 16-19 hours), and there was no significant difference in t1/2. Mean CL/F and V/F were similar for the three suppository treatments (13-15 L/hr/kg and 270-274 L/kg, respectively); values for these variables were lower with the oral formulation (CL/F = 4 L/hr/kg and V/F = 98 L/ kg), probably because of higher bioavailability.

There were no significant differences in promethazine pharmacokinetics by sex or race. In addition, the treatment differences were comparable between males and females and among black, white, and Hispanic subjects (i.e., there were no significant treatment-by-sex or treatment-by- race interactions). Overall mean pharmacokinetic variables (across treatments) for women were very similar to those for men (Table 2). Overall mean pharmacokinetic values by race are shown in Table 3. Although the difference was not significant, Hispanics had a higher overall mean Cmax and AUC than whites or blacks; this was also true for mean Cmax and AUC by treatment.

Figure 3 shows individual and mean dose-normalized Cmax and AUC0- for the four treatments. The syrup yielded the highest mean AUC0- per milligram (7.2 ng x hr/ mL), and the two 12.5-mg suppositories produced the lowest (4.1 ng x hr/mL). However, there were no significant differences among the four treatments in AUC0- per milligram. There were no significant differences among the suppository treatments in dose-normalized Cmax, but the syrup produced a significantly higher Cmax than the suppositories.

Dose-normalized promethazine Cmax (A) and AUC0- (B). Circles represent individual values, and short horizontal bars represent mean values.

Bioavailability for each suppository treatment relative to the syrup is shown in Figure 4. Mean bioavailability relative to the syrup was 70%, 97%, and 84% for the two 12.5-mg suppositories, one 25-mg suppository, and one 50-mg suppository, respectively. Individual relative bioavailabilities for the three suppository treatments ranged from less than 4% to more than 300%.

Relative bioavailability of promethazine for each suppository treatment (reference bioavailability [100%] = 50 mg [10 mL] of promethazine oral syrup). Circles represent individual values, and short horizontal bars represent mean values.

There were no serious adverse events during the study. No clinically important changes from baseline laboratory test results, vital signs, physical examination findings, or ECGs occurred. A total of 19 subjects (53%) had one or more mild to moderate adverse events during the study, including somnolence, headache, nausea, dizziness, and asthenia; all events resolved. The most common adverse events were somnolence (13 subjects [36%]) and headache (10 [28%]). Somnolence was more frequent with the 50-mg treatments (6 subjects [17%] and 8 subjects [22%] for the syrup and the suppository, respectively) than with the 25-mg treatments (2 subjects [6%] for each treatment). Headache, nausea, vomiting, dizziness, and asthenia were infrequent, and their rate was not associated with any particular treatment. Other infrequent adverse events included abdominal pain, accidental injury, back pain, rash, and injection-site pain.

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