Dose-dependent kinetics of theophylline disposition in asthmatic children (original) (raw)
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Dose-dependent kinetics for theophylline: Observations among ambulatory asthmatic children
The Journal of Pediatrics, 1980
Dose-dependent kinetics for theophylline: Observations among ambulatory asthmatic children In order to assess the clinical impact of dose-dependent kinetics for theophylline, the relationship between serum concentration and daily dosage among patients under the care of the University of Iowa Pediatric Allergy and Pulmonary Service was examined. Dosage was titrated clinically, with the final adjustment based on a serum theophylline measurement. Of 200 charts initially reviewed, 42 patients were found in whom at least two peak serum concentrations had been measured at different doses of the same theophylline preparation. In 30 (15% of initial 200) of these 42 patients', the percent change in serum concentration exceeded the percent change in dose by at least 50%. Subsequently, 300 additional charts were reviewed to identify a total of 26 patients with three steady-state serum concentrations at three different doses. Only five of these patients demonstrated a linear relationship between dose and serum concentration," the other 21 demonstrated disproportionate changes compatible with parallel first-order and dose-dependent kinetics. Thus, clinically important dose-dependent kinetics for theophylline occur in at least 15% of children, and theophylline dosage therefore must be adjusted in small increments in order to avoid disproportionately large changes in serum concentration with consequent risks of toxicity during continuous therapy.
European Journal of Clinical Pharmacology, 1981
The pharmacokinetics of theophylline following a single intravenous dose of aminophylline were determined in 8 asthmatic patients in each of the acute, the recovery and the remission phases. The overall results for mean plasma theophylline clearance (78.6 _+ 33.3 ml/kg/h), plasma theophylline half-life (4.14 +_ 1.36 h) and apparent volume of distribution (0.41 _+ 0.066 l/kg) are in accordance with previously published values. There was no general statistically significant difference in any of the pharmacokinetic parameters when results from the acute and remission phases were compared. However, certain patients showed reductions in plasma theophylline clearance in the acute phase of the illness such that a dosage regimen standardised during remission may cause toxicity if continued in the acute episode. It is suggested that monitoring the plasma theophylline levels is desirable in all patients in the acute episode.
Pharmacokinetic analysis of the disposition of intravenous theophylline in young children
The Journal of Pediatrics, 1976
Pharmacokinetic analysis of the disposition intravenous theophylline in young children of 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 mean plasma theophylline clearance was 0.100 +_ 0.036 1/kg/hr, k~ 0.49 ++_ 0.30 hr L, Btt/z 3.38 +_ 1.11 ht; atV2 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 idel~tical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetie constants predict that a maintenance dose rate for aminophylfne 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/ l. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement 'of steady state) have not yet been conducted.
The Journal of Pediatrics, 1981
Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma Completeness of absorption and fluctuations m serum theophylline concentratton were examined in 14 children, 8 fo 17 years of age t mean 12.4), with chronic asthma treated in variable sequence with a slowrelease formulation at eight-and 12-hour intervals, and plain tablets ever 3, six hours. The total fraction absorbed for the slow-release formulation was 0.98 ~ 0.07 ~mean z SEMI during the eight-hour and 0.99 = 0.04 during the 12-hour regimens. Observed fluctuations m serum concentration were closely approximated by predictions determined from absorption of single doses in adult volunteers. Available single-dose absorption data then were used to compare predicted fluctuations in serum concentration among nine eCbrmulations r18 brand names)for eight-and 12-hour dosing zn an average child and adult relimination half-lives of 3. 7 and 8.2 hours, respectively). Although predicted peak concentrations were less than twice the wough eCbr all products when given at 12-hour intervals" to an average nonsmoking adull, only two of the rime lbrmulations (both from the same manufacturer) were likely to maintain predicted fluctuations within the 10 to 20 i~g/ml therapeutic range during 12-hour dosing intervals in an average child. Most children and those adult~ with rapid elimination generally will require eight-hour dosing with the other products.
Relationship of theophylline clearance to oral dosage in children with chronic asthma
The Journal of Pediatrics, 1977
Relationship of theophylline clearance to oral dosage in children with chronic asthma Theophylline clearance was examined in 23 children with chronic asthma by administering constant intravenous infusions of theophylline until steady-state serum concentrations were documented Clearance was subsequently related to peak and trough serum concentrations during a multiple-dose oral theophylline regimen. Although theophylline clearances tended to decrease with age, considerable interpatient variability was observed Clearances correlated inversely with a standardized index of serum concentration response to oral dosage resfdting in a wide range of dosage requirements to maintain therapeutic serum concentrations of 10 to 20 ttg/ml, lntrapatient variability over an interval up to seven months, however, was acceptably small, suggesting that dosage requirements, once established for an individual, should remain relatively stable under normal conditions. Differences in serum theophylline values during a 6-hour dosing interval among children who were receiving theophylline on a continuous basis correlated with clearance and averaged 9 +_ 3 ~tg/ml (mean +_ SD), exceeding the 10 tLg/ml interval width of the therapeutic range among 40% of the children. This observation supports the clinical need for reliable sustained-release preparations of theophylline for children who are receiving continuous therapy in order to avoid unrealistically short dosing intervals.
Intraindividual variability in theophylline pharmacokinetics in subjects with mild/moderate asthma
Journal of Allergy and Clinical Immunology, 1987
Intrasubject variability in theophylline pharmacokinetics was assessed in six subjects with mild/moderate asthma. On four occasions, each separated by a minimum of 3 weeks, a 6 mg/kg intravenous aminophylline dose was infused during 30 minutes, and multiple blood samples were obtained thereafter. The pharmacokinetic parameters of clearance (CI), volume of distribution, and half-life were determined by noncompartmental analysis. There was evidence for within-subject variability in these parameters. In comparison to the first study day, CI changed by >15% in all but one subject and by >25% in two of six subjects. Changes in half-life exceeding 25% of the value observed on the first study day occurred in three of six subjects. Within-subject coefficient of variation for CI was 14.9% (range 3.9% to 33.3%) and 14.4% (range 5.8% to 24.3%) for half-life. Volume of distribution, however, was a more stable parameter with a within-subject coefficient of variation of 7.2% (range 2.3% to 11.1%). Thus, within-subject changes in the pharmacokinetics of theophylline do exist over time. These data suggest that close monitoring of patients receiving theophylline is warranted, particularly when theophylline concentrations are maintained at either extreme of the therapeutic range. (J ALLERGY CLIN IMMUNOL 1987;80:33-8.) Theophylline has recently been demonstrated to exhibit apparent random changes in pharmacokinetic disposition within the same subject.'' ^ This type of unpredictable pharmacokinetic behavior has several implications. First, from a therapeirtic standpoint, patients maintained at tiie extremes of the therapeutic range (10 to 20 p-g/ml) would require close monitoring for signs of toxicity or exacerbation of symptoms as a result of unpredictable changes in serum theophylline concentrations. Additionally, bioavailability studies depend on the CI of the study drug to remain constant between study days. A change in CI within subjects could influence the interpretation of these studies. For example, if the AUC of a drug was observed to be lower during the administration of a sustained-release preparation, as compared to that ob-
Theophylline absorption in young asthmatic children receiving sustained-release formulations
The Journal of Pediatrics, 1985
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 prepartions of sustained-release theophylline.
Oral theophylline dosage for the management of chronic asthma
The Journal of Pediatrics, 1978
Oral theophylline dosage for the management of chronic asthma Theophylline dosage requirements to maintain serum concentrations of 10 to 20 I~g/ml among asthmatic patients were examined in 156 children, ages 2 89 months to 16years, and 33 otherwise healthy adults. Using 100% bioavailable preparations, low doses were used initially and increased, if tolerated, at threeday intervals, Final dosage was based On serum theophyttine measurements which were subsequently repeated after six or more months of therapy. Dosage standardized by weight averaged 24.1 +_ 5.5 mg/ kg/day (mean + SD) among the 77 children under age 9 years. Age-related variability of weight-adjusted doses were not observed for younger children, but average dose requirements decreased progressively beyond age 9 years to 13 mg/kg/day for patients beyond 16 years of age. A #hough interpatient variability in dosage was confirmed at aH ages, intrapatient variability in requirements over an average eight-month interval were small," dosage changes to maintain therapeutic serum concentration were primarily associated with growth. These data allow age-specific guidelines for dosage recommendations based on the likelihood of optimally effective and potentially toxic serum theophylline concentrations.
Theophylline for Chronic Asthma: Rationale for Treatment, Product Selection, and Dosage Schedule
Allergy and Asthma Proceedings, 1983
Theophylline has emerged as one 0/ the mOST useful non-corticosteroid agents available for suppressing :rmptoms in the patient with chronic asthma. Maximal benefit, however, requires appreciation of the pharmacodynamics and pharmacokinetics o.l'This drug. A t concentrations between 10 and 20 mcg/ mi. optimal likelihood o.l benefit without toxiciTY is afTained and sympToms of asthma are virTualll' eliminated in many patients and are significant Zl' decreased even in paT ients requiring inhaled or oral COrTicosteroids. InrerpaTient variability in the rate ol drug elimination. however. resuiTs in a wide range o.l doses To atTain these serum concentrations. Initiation of therapy WiTh low doses and the determination o.ffinal dosage by measurement o.lserum theophylline concentration is essentialfor safe and eflective use. A simple and efficient dosing schedule has been developed that virtua/~l' eliminates problems of intolerance ol The drug and results in all buT about 1% o.l'children and almost as many adults ToleraTing theophylline without adverse effects. Sustained-release theophylline preparations, when relia-b~l' and complete~l' absorbed. o.ffer major therapeutic advantage by minimizing fluctuations in serum concen-Pro.