Theophylline Dose-Concentration Relationship of a 12-Hourly Nuelin SA Regimen Supplemented with Nocturnal Nuelin Liquid in Healthy Volunteers

Abstract

Twelve healthy male volunteers who were diurnally active between 05:00 and 23:00 took part in a randomized, multiple-dose, double-blind, four-way, crossover study to determine the relationship between the dose of a nonsus-tained-release theophylline (NSRT) formulation added to the evening administration of a 12-hourly sustained-release theophylline (SRT) regimen and the elevation of the early morning (between 02:00 and 05:00) steady-state plasma theophylline concentration. The four treatments were 250 mg Nuelin SA (sustained-release theophylline) every 12 h plus either placebo or Nuelin liquid (non-sustained-release theophylline) equivalent to 100 mg, 200 mg, or 300 mg of theophylline. Without evening supplementation (placebo), the early morning plasma theophylline concentrations were 13% lower than the average 24-h concentration. but with evening supplementation the early morning plasma theophylline concentration could be raised up to and above the average 24-h Concentration. A prediction equation for the early morning plasma theophylline concentration as a function of the additional evening dose of Nuelin liquid, and of the steady-state evening trough plasma theophylline concentration without evening supplementation, was established. This prediction equation can be used to determine the additional evening dose of Nuelin liquid (administered at 19:00) needed to reduce early morning bronchoconstriction in asthmatic patients who are on a 12-hourly Nuelin SA (drug administered at 07:00 and 19:00) regimen.

Key Words:

• Nocturnal asthma
• “Morning dip”
• Pharmacokinetics
• Unequal twice-daily dosing
• Nocturnal excess
• Sustained-release theophylline
• Immediate-release theophylline