Cathy Klech Gelotte

An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine

ABSTRACT Phenylephrine hydrochloride (HCl) is a decongestant available in over‐the‐counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended‐release salt, which allowed dosing every 8–12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed. HighlightsPhenylephrine is available as nonprescription, single‐ and combination‐ingredient products.Although extended release, phenylephrine tannate had similar plasma concentrations as the HCl salt from 2 to 5 h after dosing.When dosed in combination, acetaminophen increased AUC∞ and Cmax of phenylephrine about 50% and 200%, respectively.Food delayed the adsorption of phenylephrine, but did not affect total exposure.

Single‐Dose Pharmacokinetic Study of Diphenhydramine HCl in Children and Adolescents

Diphenhydramine pharmacokinetics were characterized following a single oral dose in children aged 2 to 17 years using a weight‐ and age‐based dosing schedule with more tiers than the current age‐based dosing schedule recommended by the nonprescription drug monograph. This study was conducted in 42 subjects, aged 2 to 17 years. Doses were based on a weight‐age dosing schedule, ranging from 6.25 to 50 mg. An oral dose was administered with water about 2 hours after a light breakfast. Plasma samples were obtained up to 48 hours after dosing and analyzed for diphenhydramine. Pharmacokinetic parameters were estimated using noncompartmental methods, and the relationship of oral clearance with age was assessed using linear regression. Over an 8‐fold range of doses, Cmax and AUC increased ∼90 % to ∼140% across age groups, with a similar Tmax (1.5 hours). Oral CL/F increased with age, but after allometric scaling, no maturation‐related change in CL/F was apparent. Mild somnolence was the most commonly reported adverse event (95% of the subjects). A weight‐age dosing schedule using an 8‐fold range of doses achieved Cmax and AUC that increased about 2‐fold across age groups. No effect of maturation on CL/F was observed after allometric scaling.

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies

OBJECTIVE Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. METHODS Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. RESULTS A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. CONCLUSIONS Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Multiple-Dose Pharmacokinetics and Safety of an Ibuprofen-Pseudoephedrine Cold Suspension in Children

Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 ± 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 ± 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 ± 2.2 mL/kg/min and Vd/F was 2.52 ± 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.