Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma

The single- and multiple-dose absorption characteristics of a new sustained-release theophylline preparation, which has been formulated for once per day dosing in adults, were investigated in children aged 8 to 14 years. Four single doses were studied, each dose separated by 1 week. During steady state the preparation was given once daily in the morning for 1 week, and serum theophylline concentration was determined through two dosing intervals (48 hours). The product showed excellent sustained-release characteristics and consistent absorption profiles, which were not affected to any clinically important extent by the intake of various meals. After single doses, only 77% to 91% of the product was absorbed during the first 28 hours after dosing. However, bioavailability was complete both after single doses and during steady state. Eight of 14 children had steady-state fluctuations in serum theophylline levels of less than 90% when given doses once daily. Steady-state day-to-day variations in serum theophylline profiles were small in all patients except one, in whom differences up to 33 mumol/L (6 micrograms/mL) were seen (8 hours after dosing). We conclude that this formulation is completely absorbed at a sufficiently slow and consistent rate to permit acceptable fluctuations in absorption with once daily dosing for many, but not all, patients. However, it should not be used in very young children until bioavailability has been studied in this age group.     

Theophylline absorption in young asthmatic children receiving sustained-release formulations

Theophylline absorption from sustained-release formulations intended for administration every 8 hours and every 12 hours was examined in children ages 2 to 6 years during multiple dosing intervals. By generally applied measurements, including mean serum theophylline concentration, bioavailability over a single daytime dosing interval, and percent change in serum theophylline concentration over a single dosing interval, the preparations did not differ. However, over multiple dosing intervals, the 8-hour preparation varied in rate and extent of absorption, with subsequent large variations in serum theophylline concentrations. The 12-hour preparation, on the other hand, was completely bioavailable during each dosing interval, although the rate of absorption did differ from day to night, and was associated with generally acceptable changes in serum concentrations. Thus, analysis of dose-to-dose absorption was required to reveal the differences between the two study preparations. This indicates that traditional analysis of a single daytime dosing interval may be inadequate in the evaluation of preparations of sustained-release theophylline.     

Bioavailability of a slow-release theophylline capsule given twice daily to preschool children with chronic asthma: comparison with liquid theophylline

The reliability of slow-release theophylline products in young children has been questioned. Therefore, we studied the bioavailability of a commonly prescribed slow-release theophylline formulation (Slo-Bid Gyrocaps), administered twice daily by sprinkling the beads on applesauce. Serial measurements of serum theophylline concentrations were obtained during steady state in eight children (ages 1.6 to 5 years) after receiving a reference liquid theophylline product every six hours and also while receiving the slow-release product every 12 hours. The morning dose of slow-release theophylline was given before the child had eaten, and the evening dose was given two hours after supper. The extent of absorption of the slow-release product was 98.3 +/- 20.2% (mean +/- SD) relative to the liquid reference. The serum concentration fluctuations, expressed as percentage of the measured trough, did not differ between the two products: 108 +/- 59% v 129 +/- 97% (P greater than .05) for reference and slow-release products, respectively. Three of the eight patients had unacceptably large fluctuations (greater than 100%) while receiving the slow-release regimen, and two of these three had unacceptable fluctuations while receiving the liquid reference. The rate of absorption was slower after the evening dose of slow-release product (postprandial), resulting in significantly smaller fluctuations, and lower peak concentrations. Time to peak concentration while receiving the slow-release regimen varied from two to four hours after the evening dose and from two to eight hours after the morning dose. However, the average difference between the peak concentration and the four-hour measurement after the morning dose was only 0.3 microgram/mL (range 0 to 2.6 micrograms/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

EVALUATION OF A NEW SUSTAINED-RELEASE THEOPHYLLINE TABLET FOR CHILDREN

Abstract. Selvig, K., Alme, A., Rugs tad, H. E., Aas, K. and Bjerve, K. S. (Institute of Clinical Biochemistry, the Allergy Institute Voksentoppen, Department of Paediatrics and Department of Clinical Pharmacology, Rikshospitalet, Oslo 1, Norway). Evaluation of a new sustained-release theophylline tablet for children. Acta Paediatr Scand, 70: 929, 1981.-A new, low dose sustained-release tablet of theophylline has been developed in order to facilitate a correct dose regimen in asthmatic children treated with theophylline. The formulation (Euphyllin® retard mite w/groove) contains 128 mg of theophylline, and can easily be divided. The extent of bioavailability in adults is 0.91, and the peak serum concentration is reached after 8.7 h. 25 children treated with plain theophylline tablets were followed when changing to the sustained-release tablets. Compared to the plain tablets, the serum theophylline concentration before the morning dose was 29 μmol/l higher (range 12–51) when the same daily dose was given as a sustained-release preparation. The serum concentration fluctuations during one dosing interval were reduced with 13 μmol/l (0–26). Mild gastrointestinal side effects reported by the children when using the plain theophylline tablets all disappeared on changing to the sustained-release tablets.     

Theophylline for chronic asthma: rationale for treatment, product selection, and dosage schedule

Although theophylline has been available for over 50 years, only in the last 10 years has an understanding of its pharmacodynamics and pharmacokinetics permitted its use with optimal efficacy and safety. Serum concentrations between 10 and 20 mcg/ml stabilize the hyperreactive airways that characterize asthma as measured by exercise-induced bronchospasm and clinical suppression of asthmatic symptoms, even among those patients not sufficiently controlled with bronchodilators alone who consequently require inhaled or oral corticosteroid therapy. Careful dosage titration prevents adverse effects, especially when final dosage is guided by measurement of serum concentration. Large interpatient variability in dose requirements is seen, but there is normally little intrapatient variability except when physiologic abnormalities or drug interactions alter the elimination of theophylline. Rapid elimination, rapid absorption from conventional products, and the narrow therapeutic range for theophylline result in clinically important fluctuations in serum concentration and consequent effect unless unrealistically short dosing intervals are maintained or reliable slow-release formulations are used. Slow-release theophylline products vary, however, and performance often does not match the manufacturer's claims. Assessment requires characterization of absorption rate, which then allows prediction of fluctuations in serum concentration at specified dose intervals and defined rates of elimination.     

Postoperative morphine infusion in newborn infants: assessment of disposition characteristics and safety

Twelve newborn infants were given morphine intravenously for postoperative analgesia. They received a continuous infusion of 6.2 to 40 micrograms/kg/hr for 9 to 105 hours (mean +/- SEM 59.5 +/- 10.2 hours); in four the infusion was preceded by a loading dose of 50 to 100 micrograms/kg. Morphine plasma concentrations correlated with the rate of infusion, but with large variability. There was a tendency for plasma morphine concentrations to decrease in some patients receiving a constant infusion rate, suggesting improvement in morphine clearance rate. Elimination half-life of morphine (13.9 +/- 6.4 hours) was significantly longer than in older children and adults (about 2 hours). Similarly, morphine concentrations in neonates receiving 20 micrograms/kg/hr for 24 hours were three times higher (52 +/- 31 ng/ml) than in older children receiving the same schedule. Two infants who received 32 and 40 micrograms/kg/hr, respectively, developed generalized seizures. Because of the apparently greater sensitivity to morphine and the lower elimination rate in newborn infants, the infused dose should not exceed 15 micrograms/kg/hr.     

Percutaneous administration of theophylline in the preterm infant

The preterm infant's skin is a poor barrier to the absorption of chemical agents. The possibility of turning this to the infant's advantage was explored by using the percutaneous route to administer theophylline. A standard dose of theophylline gel, equivalent to 17 mg anhydrous theophylline, was applied to an area of skin 2 cm in diameter over the upper abdomen under an occlusive dressing, and serial theophylline levels were measured; 25 studies were performed in 20 infants of less than or equal to 30 weeks gestation. Therapeutic theophylline levels (greater than 4 mg/L) were achieved in 11 of 13 infants who had not previously received the drug, and were maintained for up to 72 hours. In 12 studies in infants who were previously receiving aminophylline intravenously, theophylline levels were maintained for up to 70 hours. There was a significant decline in the amount of theophylline absorbed in the first 24 hours after application as the infant's postnatal age increased, but satisfactory blood levels were achieved in infants up to 20 days of age. The percutaneous route is a feasible method of administering theophylline in preterm infants.     

Comparison of New Sustained-Release Theophylline (E-0686) and Theo-Dur

New sustained-release theophylline (E-0686) was administered to asthmatic children to study changes in serum theophylline level and its reproducibility. Results are as follows:

• 1) t-Max. of E-0686 was shorter than that of Theo-Dur, however, E-0686 could maintain a satisfactory serum theophylline level at 12 hours on a single dose.
• 2) A steady state was reached after three days on a multiple dose of E-0686. P-T difference of E-06 was 5.17 μg/ml, which could be sufficient for sustained-release theophylline.
• 3) Changes in serum theophylline level of E-0686 was highly reproducible.

     

Apparent inconsistent theophylline absorption from sustained release capsules

Sustained release theophylline products can improve compliance and symptom control in children with asthma. This study examines theophylline serum concentration monitoring in pediatric patients. Fifteen children with documented asthma were randomized to receive either Slo-bid Gyrocaps or Theo-dur Sprinkle for 1 month, and then crossed over to the other product. On the last day of each study period, theophylline serum concentrations were obtained prior to the morning dose and 4 hours later. In two patients receiving Theo-dur Sprinkle and six with Slo-bid Gyrocaps, the 4-hour serum concentration was lower than the pre-dose concentration. The change between the pre-dose and post-dose serum concentrations for Theo-dur Sprinkle ranged from a decrease of 2.8 mg/L to an increase of 4.9 mg/L, and, for Slo-bid Gyrocaps, from a decrease of 4.6 mg/L to an increase of 10.5 mg/L. The inconsistent theophylline absorption with each product makes dosage adjustment difficult.     

Pharmacokinetic analysis of the disposition of intravenous theophylline in young children.

The disposition of a single intravenous dose of theophylline, 3.2 mg/kg, was studied using a high-pressure liquid chromatographic assay in ten asthmatic children one to four years of age. The man plasma theophylline clearance was 0.100 +/- 0.036 l/kg/hr, kel 0.49 +/- 0.30 hr-1, betat1/2 3.38 +/- 1.11 hr, alphat1/2 0.13 +/- 0.09 hr, and V1 0.25 +/- 0.13 1/kg. Plasma theophylline clearance was approximately 40% greater in these children than that reported in adults, mainly due to an increased rate of drug elimination. Large interindividual differences were observed. Analysis of data using either a two- or one-compartment model yielded almost identical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetic constants predict that a maintenance dose rate for aminophylline of 30 mg/kg/day, after a loading dose of 5.6 mg/kg, would rapidly achieve and maintain a mean steady-state plasma concentration of theophylline of 10 mg/1. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement of steady state) have not yet been conducted.     

Single-dose pharmacokinetics of imipenem in children

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin) was evaluated in 13 pediatric patients (mean age 5.2 +/- 3.5 years). Imipenem was administered in combination with cilastatin as either a 10 mg/kg or 25 mg/kg dose (not to exceed 500 mg) over 15 minutes. Plasma disposition in children was best described by a two-compartment open model. The distribution phase was rapid (t1/2 lambda 1 = 0.18 hours) and was followed by a monoexponential elimination phase (t1/2 lambda 2 = 1.2 hours). The calculated value for the apparent volume of distribution (0.66 L/kg) was similar to that of total body water. The total plasma clearance was rapid (0.36 L/hr/kg). Direct proportionality was exhibited between administered dose and either resultant plasma concentration or area under the plasma concentration versus time curve. Comparison of imipenem plasma pharmacokinetic data derived from these children with data reported from adult subjects revealed disparities for both the apparent volume of distribution and plasma clearance. Based on preliminary pharmacokinetic simulations using parameters generated from our study, a 25.0 mg/kg dose of imipenem administered every 6 hours appears adequate for initiation of therapy in children.     

Aminophylline dosage in acute severe asthma

In 27 cases of acute severe asthma, a loading dose of 5 mg/kg of aminophylline (omitted if already receiving oral theophylline) followed by a continuous infusion of 1 mg/kg per hour gave satisfactory theophylline levels at 4 h and 24 h. Theophylline clearance rates varied widely, vomiting was common, but unrelated to blood theophylline levels.     

Plasma xanthine levels in low birthweight infants treated or not treated with theophylline.

The use of theophylline in the management of apnoea in the newborn was studied in 33 preterm infants. Infants received a dose of 3 mg/kg, 13 of them every six hours, the remaining 20 every eight hours. All the infants had significantly fewer apnoeic episodes. In a pharmacokinetic study, the half life of theophylline was 30.3 +/- 7.2 hours and the clearance rate was 23.9 +/- 5.06 ml/kg per hour (means and SD). The plasma theophylline level remained constant at between 13 and 15 mg/l from the 5th day of treatment but, at the same time, the plasma levels of caffeine rose to a mean level of 4.4 mg/l. Caffeine was detectable in plasma at birth, and in preterm infants not receiving theophylline; plasma levels of caffeine tended to be similar to the levels in their mothers' milk. These observations have led to clear conclusions on the optimum timing and dosage of theophylline, and on the need to monitor plasma levels of both theophylline and caffeine in newborn infants treated with theophylline.     

Paroxysmal supraventricular tachycardia during theophylline therapy in a premature infant

An episode of supraventricular tachycardia occurred in an infant born at 31 weeks' gestation after three days of therapy with theophylline 3.5 mg/kg every six hours. The infant had a plasma theophylline half-life of 24.7 hours and a low plasma theophylline clearance of 12.7 ml/kg/hour. The plasma theophylline concentration at the time of the arrhythmia was about 42 mg/l. The extent of drug accumulation with these kinetic characteristics is emphasized. Serious adverse effects due to theophylline may occur with few signs of symptoms of impending toxicity. Plasma theophylline concentration measurements are valuable in avoiding such toxicity.     

Aminophylline therapy in children: guidelines for dosage

The oral dosage of aminophylline required for therapeutic "trough" serum theophylline levels was studied in 150 children, 16 months to 19 years old (mean 8.28 years). Dosage requirements tended to be higher for children under 10 years, but marked person-to-person variability in the relation of dose to serum level was seen at all ages. Individual patients generally maintained consistent serum levels when receiving unchanging doses, although intercurrent disease sometimes disrupted this relationship. Individualization of oral dosage based on frequent serum measurements is necessary to maintain theophylline levels in the therapeutic range and to avoid toxicity.     

Altered theophylline clearance during an influenza B outbreak

During the 1980 influenza B outbreak in King County, Washington, 11 children whose asthma had previously been controlled with a stable theophylline dose, developed theophylline toxicity on this same dose. Two had seizures, eight had nausea and vomiting, and three had headaches. All had clinical evidence of a febrile viral illness. The toxicity appeared to be related to decreased theophylline clearance, which gradually returned to preillness levels over a period of one to three months. Six of ten children had serologic evidence of influenza B, which is presumed to be the cause of the altered clearance. In children receiving chronic theophylline therapy, symptoms of vomiting, headaches, or seizures during a viral illness may be due to theophylline toxicity rather than the virus. Such patients should have an immediate serum theophylline determination, even if previous levels have been in the therapeutic range.     

Sustained-release terbutaline vs sustained-release theophylline in young patients with asthma

Twenty patients with asthma (mean age, 10.9 +/- 2 years) entered a six-week, randomized, double-blind, crossover comparison of sustained-release (S-R) terbutaline sulfate (Bricanyl Durules) vs S-R theophylline (Theo-Dur). In each two-week study period each patient received S-R theophylline twice daily in doses previously adjusted to give serum theophylline concentrations in the range of 10 to 20 mg/L (56 to 111 mumol/L); or S-R terbutaline sulfate, 5 mg twice daily; or S-R terbutaline sulfate, 7.5 mg twice daily. All treatment regimens produced significant improvement in one or more pulmonary function test values compared with prestudy values. The incidence of acute asthma episodes were similar during each treatment regimen. No clinically significant difference occurred between the regimens for daily symptom scores, peak expiratory flow rates, or use of a terbutaline metered-dose inhaler. At the end of the theophylline treatment period, the mean (+/- SD) theophylline level 12 to 14 hours after the last dose was 10.1 +/- 3.3 mg/L (56 +/- 18 mumol/L); at the end of the terbutaline treatment periods, the mean trough terbutaline levels were 2.22 micrograms/L (9.9 +/- 4.4 nmol/L) (S-R terbutaline sulfate, 5 mg twice daily) and 3.07 micrograms/L (13.7 +/- 5.4 nmol/L) (S-R terbutaline sulfate, 7.5 mg twice daily). Adverse effects, including tremor, occurred with similar frequency during all three drug regimens. Sustained-release formulations of theophylline and terbutaline, in the dosages studied, provided comparable control of asthma symptoms.     

Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.     

Pharmacokinetic profile of caffeine in the premature newborn infant with apnea.

The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+/- SE) AV d, t 1/2, ke1, and clearance following a single intravenous dose were 0.916 +/- 0.070 1/kg, 102.9 +/- 17.9 hours, 0.009 +/- 0.001/hours and 8.9 +/- 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of 10 mg/kg. Cpss of caffeine in infants given a high empirical dose (11.2 +/- 1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean = 13.7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/kg/day administered as a single dose for the treatment and prevention of neonatal apnea.     

Triglycerides, free fatty acids, free fatty acids/albumin molar ratio, and cholesterol levels in serum of neonates receiving long-term lipid infusions: controlled trial of continuous and intermittent regimens

We compared intermittent (8 hours/day) versus continuous (24 hours/day) isocaloric lipid infusion regimens in 28 neonates. The lipid dose was increased incrementally by 0.5 gm/kg/day to either 3 gm/kg/day or until fat contributed 40% of daily calories. Serum total triglycerides, free fatty acids, free fatty acids/albumin molar ratio, and total cholesterol levels were measured prior to the daily lipid infusion, at the end of the intermittent infusion, and at 8 hours during the continuous infusion. Neonates less than 32 weeks postconception had significant fluctuation of triglycerides, free fatty acids, and free fatty acids/albumin molar ratio during the intermittent regimen at all lipid doses, but not during the continuous regimen. Neonates greater than or equal to 32 weeks postconception had significant fluctuation of serum triglycerides, free fatty acids, and free fatty acids/albumin molar ratio during the intermittent regimen with a lipid dose greater than or equal to 2 gm/kg/day, but not during the continuous regimen at all lipid doses. Serum free fatty acids correlated closely with serum triglycerides during both regimens (r = 0.89, P less than 0.001). Serum total cholesterol rose with increasing lipid doses during both regimens (f = 8.16, P less than 0.05). We conclude that neonates less than 32 weeks postconception tolerate the continuous regimen better than the intermittent regimen at all lipid doses; neonates greater than or equal to 32 weeks postconception tolerate both regimens well at lipid dose less than 2 gm/kg/day, but tolerate a continuous regimen better with lipid dose greater than or equal to 2 gm/kg/day.