Steady-state evaluation of twice-a-day dosing of a new sustained-release theophylline preparation for young children

We studied the absorption properties of a new sustained-release theophylline, Theo-Dur Sprinkle® (TS), to see if this formulation when given on a b.i.d. basis results in acceptable steady-state theophylline levels in children with asthma. Twelve patients (ages 5-8 years), after multiple TS dosing, had serum theophylline levels determined over a 10-hr period after a morning TS dose. Fluctuations in serum theophylline concentrations were acceptable with the observed mean percent peak-to-trough fluctuation [(peak -trough/trough) x 100] being 53%. Patients required higher than usually recommended theophylline doses to obtain therapeutic levels, suggesting incomplete absorption of TS; this was documented with one patient using a 100% bioavailable theophylline product as a comparison.     

Once-daily versus twice-daily dosing of theophylline. A decision analysis approach to evaluating theophylline blood levels and compliance

The question of whether to prescribe once-daily or twice-daily theophylline was investigated using decision-analysis techniques with sensitivity procedures. While the relative efficacies of the two theophylline preparations have been examined in a number of studies, previous efforts have not assessed the impact of compliance on therapeutic effectiveness. When a blood theophylline level of 10 to 20 micrograms is taken to constitute the therapeutic range, twice-daily has been shown to yield 15% greater efficacy than once-daily dosing. However, results of the present investigation suggest that a drop in compliance greater than 4 to 14%, associated with once- versus twice-daily dosing, would be sufficient to obliterate the apparent advantage of the twice-daily preparation. The existing empirical evidence suggests that selecting twice-daily over once-daily dosing will incur a drop in compliance that is substantially greater than 14%. Consequently, when the impact of compliance is incorporated into a decision analysis, once-daily dosing is favored over twice-daily dosing for most patients. The decision will favor twice-daily theophylline only in the unusual case in which continuity of contact with a given patient provides strong evidence that he/she is more than 80% likely to comply with the twice-daily regimen. Decision analyses applied to this topic would benefit greatly from better studies of compliance in asthmatic patients and more careful correlations of symptoms with varying medication usage.     

Once-daily dosing of aminoglycoside antibiotics

Improved understanding of the pharmacodynamics and toxicity of aminoglycoside antibiotics has resulted in the study of once-daily dosing regimens. Although studies have suggested a therapeutic advantage and possibly a decrease in toxicity with once-daily administration, these effects have been modest. The cost savings associated with once-daily aminoglycoside administration, however, makes this approach appealing. Although a syndrome of fever, tachycardia, hypotension, and rigors has been associated with once-daily dosing of gentamicin, this appears to have been the result of impurities in the antibiotic from a single offshore supplier. This syndrome has not been associated with other aminoglycoside antibiotics, and the FDA has now withdrawn its recommendation that once-daily aminoglycoside use be avoided. As with any medical regimen, the decision to use once-daily dosing of aminoglycoside agents must take into account special patient characteristics and the disease state being treated. Although once-daily dosing appears effective in limited studies in children, in individuals with neutropenia, and in individuals with cystic fibrosis, its role in gram-positive coccal endocarditis and in individuals with altered volumes of distribution remains uncertain. Further data are needed to clarify the role of once-daily dosing in these situations.     

Once-daily and twice-daily dosing of p-aminosalicylic acid granules

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.     

Clinical and pharmacological observations on a new microcrystalline theophylline preparation

Tablets containing 250 mg of microcrystalline theophylline were given at 6-hourly intervals for 6 days. Minimum plasma theophylline concentrations in eight patients averaged 36.6 +/- 5.4 mumol/l (1 mumol = 0.18 mg), and the corresponding maximum concentration were 81.8 +/- 10.6 mumol/l. In 11 patients, studied after a single 250 mg dose, significant improvements in PEF and FEV1 were observed, in spite of maximum concentrations averaging only 38.8 +/- 2.2 mumol/l, which is below the commonly regarded lower limits of the therapeutic range. Nine of the 11 patients complained of side effects and in three patients a reduction in dose was necessary. In four volunteers given a single dose of 250 mg the plasma concentration of theophylline were not particularly affected by whether the tablets were taken fasting or postprandial.     

Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC(50)) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation.     

A randomized controlled clinical trial of pharmacokinetic theophylline dosing

Ninety-one patients admitted to hospital with acute air-flow obstruction and requiring theophylline therapy were randomly assigned to either a monitored or a control group. Intravenously administered and subsequent orally administered theophylline dosages for patients in the monitored group were adjusted daily on the basis of each patients's estimated theophylline clearance; dosages for control patients were determined by attending physicians, using knowledge of theophylline serum concentrations. During intravenous therapy, fewer monitored than control patients had serum theophylline concentrations in the toxic range (18.9 versus 37.8%, p = 0.04), and during subsequent oral therapy more monitored than control patients had serum theophylline concentrations in the therapeutic range (71.1 versus 44.4%, p = 0.018). There was a trend for peak expiratory flow rates to normalize more quickly in monitored patients, and their mean duration of hospital stay was shorter (6.3 versus 8.7 days, p = 0.029). Two patients in the control group died; both had theophylline concentrations above 25 micrograms/ml and clinical toxicity. No serious side effects were observed in the monitored group. With pharmacokinetic individualization of theophylline dosage, more patients achieved serum concentrations in the therapeutic range, and there was a tendency for more rapid clinical improvement.     

Once-daily sustained-release theophylline reduces diurnal variation in spirometry and symptomatology in adult asthmatics

In 22 adult asthmatics (mean age, 55.2 +/- 15.4 yr), we compared Uniphyl given once a day to Theo-Dur given twice a day using a randomized, double-blind, two-phase crossover trial. All patients demonstrated acute bronchodilator responsiveness (FEV1 increase greater than 15%) to inhaled salbutamol and were dependent upon both orally administered theophylline and inhaled salbutamol at time of entry. Each phase lasted 9 days, the first 2 days of which were a theophylline washout. Uniphyl was given once a day at 8 P.M. and Theo-Dur was given twice a day at 8 A.M. and at 8 P.M. For each patient, the total daily theophylline dose was the same during both phases. Asthma symptoms, drug side effects, and PEFR were recorded at 8 A.M. and at 4 and 8 P.M. each day. On Days 7, 8, and 9 of each phase, serum theophylline concentrations were measured and spirometry was performed at 8 A.M. and at 4 and 8 P.M. The results demonstrated significant differences in both pharmacokinetic and clinical efficacy between the 2 drugs. Uniphyl produced greater "peak" and lower "trough" theophylline concentrations than did Theo-Dur, although both lower "trough" theophylline concentrations than did Theo-Dur, although both drugs maintained concentrations within the accepted therapeutic range. In contrast to the pharmacokinetic findings, Uniphyl was associated with significantly less fluctuation in pulmonary function throughout the day, and the values at 8 A.M. for FEV1, PEFR, and wheeze demonstrated significant clinical efficacy in favor of Uniphyl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability and pharmacokinetics of a new controlled-release theophylline preparation in the form of capsules containing pellets

The bioavailability and pharmacokinetics of a new controlled-release theophylline preparation in the form of capsules containing pellets of coated drug were studied in 10 healthy subjects. Results showed that the bioavailability of this preparation is complete after oral intake of a single dose, while after repeated administrations (300 mg b.i.d.) theophylline serum levels are constantly within the therapeutic range (10-15 mg/l) with small fluctuations over 12 h. Side effects were not observed.     

Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study

OBJECTIVE: To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. DESIGN: Open-label, multi-dose, pharmacokinetic pilot study. PATIENTS: Seven HIV-1-infected individuals who were treated with saquinavir hard gelatin capsules 400 mg twice daily + ritonavir liquid formulation 400 mg twice daily were switched to saquinavir soft gelatin formulation 1600 mg once daily in combination with ritonavir liquid formulation 200 mg once daily (day 0). Patients were instructed to ingest saquinavir and ritonavir simultaneously in the morning and with a meal. METHODS: Steady-state pharmacokinetics of saquinavir and ritonavir were assessed during a 24 h dosing interval after 2 weeks of continued therapy (day 14). Plasma saquinavir and ritonavir concentrations were measured using a validated high performance liquid chromatography assay. In addition, plasma HIV-1 RNA, and fasting total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were measured on days 0 and 14. A non-compartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC[0-24h]), the maximum and trough plasma concentrations (Cmax and Cmin), the time to reach Cmax (Tmax), the elimination half-life (t1/2), the apparent clearance (Cl/F), and the apparent volume of distribution (V/F). RESULTS: Median (range) values of the pharmacokinetic parameters for saquinavir after 2 weeks of treatment were: AUC[0-24h], 19,802h* ng/ml (3720-74,016); Cmax, 2936 ng/ml (573-6848); Cmin, 84 ng/ml (11-854); Tmax, 3.5 h (3.0-4.0), t1/2, 6.8 h (4.6-10.2); Cl/F, 81 l/h (22-430); V/F, 1189 l (215-3086). Ritonavir concentrations were always below the 90% effective concentration of 2100 ng/ml (median Cmax, 1323 ng/ml; range, 692-1528 ng/ml). No significant changes were observed for total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels between days 0 and 14 (P > or = 0.24). In six out of seven patients the fasting serum triglyceride levels were lower 2 weeks after the treatment switch (median decrease was 32%, P = 0.03). No significant changes in plasma HIV-1 RNA concentrations were observed between days 0 and 14. The regimen was generally well tolerated. CONCLUSIONS: This pharmacokinetic study indicates that the combination of 1600 mg of saquinavir (soft gelatin capsules) and 200 mg of ritonavir (liquid formulation) in a once-daily dosing regimen generally results in therapeutic plasma concentrations of saquinavir. Due to the large interindividual variation in saquinavir exposure, the monitoring of saquinavir concentrations in plasma is warranted. These pharmacokinetic findings rationalize the further clinical evaluation of once-daily dosing of this combination of protease inhibitors.     

Comparison of a new sustained-release theophylline preparation, TheoBeads, with Theo-Dur tablets in children with asthma

A new, slow-release theophylline formulation for children, TheoBeads, which has the potential for once-daily dosing, has become available. We report the results of a study of pediatric patients whose medication was changed from Theo-Dur tablets b.i.d. to TheoBeads q.d. Forty-nine children with asthma (aged 6-12 years) were treated with b.i.d. Theo-Dur to produce therapeutic maximum and minimum concentration levels (i.e., 8-20 micrograms/ml). Approximately half the patients were then transferred to TheoBeads given q.d. at the same total daily dose and retitrated; seven patients needed to be changed to b.i.d. dosing due to unacceptable fluctuations. The other half of the patients continued on b.i.d. Theo-Dur. Following at least 5 days of steady-state dosing, serum theophylline levels were assayed over a 24-hour period. It was found that: 1. Children changed to q.d. TheoBeads showed no change in their overall asthma control based on clinical diary entries and peak flow measurements. 2. Lower Cmax and Cmin theophylline levels and a smaller area under the curve were noted for patients taking q.d. TheoBeads compared to those taking b.i.d. Theo-Dur. 3. Administration of TheoBeads q.d. resulted in a significantly larger overall peak-to-trough fluctuation and a higher percentage of patients with subtherapeutic theophylline levels in the second 12-hour period than did b.i.d. Theo-Dur administration. In summary, when children receiving b.i.d. Theo-Dur were transferred to q.d. TheoBeads, they did not maintain even and sustained therapeutic theophylline levels, although asthma control was not adversely affected during the short period of observation.     

Effect of empiric dosing on blood levels of theophylline and phenytoin

To evaluate empiric dosing guidelines for aminophylline and phenytoin in the management of acute exacerbations of obstructive lung disease and seizure disorders, we utilized an emergency department (ED)-based EMIT system to measure stat plasma theophylline and phenytoin levels in patients intended to receive these drugs. Plasma drug level results were available prior to initiation of therapy. Of the patients evaluated, 45 of 163 (27.6%) aminophylline patients and 21 of 73 (28.7%) phenytoin patients were projected to have plasma concentrations below the recommended therapeutic range if empiric dosing schedules were employed. In addition, 39 of 163 (23.9%) aminophylline and 10 of 73 (13.7%) phenytoin patients, had they received these drugs empirically, would have had plasma theophylline and phenytoin levels in excess of the recommended therapeutic range using empiric dosing. We conclude that the use of empiric dosing guidelines for aminophylline and phenytoin in the ED do not reliably produce therapeutic plasma concentrations. The development of a stat drug analysis laboratory in the hospital or within the ED would improve the effectiveness and safety of these acutely used drugs with narrow therapeutic ranges.     

Bioavailability of a once daily-administered theophylline preparation. A comparison study

To evaluate the bioavailability of a new theophylline preparation suitable for once-a-day (od) oral administration, we performed a nonrandomized crossover study in which the absorption of the OD and a standard twice-a-day (bid) preparation were compared. Eight stable asthmatic patients, after having achieved steady-state, received an average of 975 mg of OD preparation at 8 PM. The protocol was later repeated with the same subjects receiving 487.5 mg of the bid preparation at 8 PM and again at 8 AM using the same total dose. The maximal mean serum concentrations were 15.5 +/- 1.6 (SEM) micrograms/ml for the od preparation on the 8th hour and 12.7 +/- 2.2 for the bid regimen. The trough level was 7.4 +/- 1.2 micrograms/ml for the od regimen and 10.6 +/- 1.6 for the bid regimen. With either regimen, therapeutic theophylline levels could be observed throughout the 24-hour study period. Anhydrous theophylline may be administered as a single daily dose agent.     

A critique of dosing strategies for beta-2 adrenergic agents and theophylline

Bronchodilator therapy today presents the practitioner with many choices in the use of theophylline compounds and beta-2 adrenergic agents. There is a logical progression in combining these agents as the disease severity increases. Clinical studies support the use of an inhaled beta-2 agent (when feasible) on a regular schedule as the primary therapy. The technique of sequential inhalation maximizes its effect. Combination with a systemic bronchodilator may provide further bronchodilation. A further escalation of therapy is obtained by combining oral theophylline with an oral beta-2 agent, advancing to full doses of each as needed and as tolerated. However, the combination of suboptimal doses of each produces considerable bronchodilation at a minimum of risk. Theophylline can be prescribed at “full” doses when attention is paid to host factors that influence its metabolism. Guidelines are listed for its acute and chronic use and serum theophylline determinations recommended to facilitate this. Low trough levels of rapidly absorbed oral bronchodilators, particularly beta-2 agents, pose a danger to certain severe asthmatics, especially when the night-time hiatus of a “q.i.d.” or “t.i.d.” dosing schedule coincides with marked circadian nocturnal bronchospasm. This problem deserves better kinetic definition and more attention. The use of sustained-release preparations or more frequent dosing of smaller amounts will reduce this danger. Other problems discussed are the questions of beta tachyphylaxis or tolerance, treatment of the life-threatening asthma attack, and the use of bronchodilators in the COPD patient with “fixed” obstruction.     

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less than or equal to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater than or equal to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less than or equal to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.