Leslie Hendeles

Theophylline A “State of the Art” Review

Theophylline is a bronchodllator and respiratory stimulant that is effective in the treatment of acute and chronic asthma, Cheyne‐Stokes respirations, and apnea/bradycardia episodes in newborns. It is also used as an adjunct in the treatment of congestive heart failure and acute pulmonary edema, but it has no established efficacy in patients with chronic irreversible airways obstruction. Benefits and risks from theophylline relate directly to serum concentration, which is a function of both dose and elimination characteristics of the drug in an individual patient. When used to treat acute symptoms, an initial loading dose based on a mean volume of distribution is required to rapidly obtain maximum bronchodilator effect. Because of large interpatient differences in elimination, constant intravenous infusion rates for continued therapy must be guided by monitoring serum theophylline concentration at intervals until a steady‐state serum concentration is reached within the 10–20 μg/ml therapeutic range. Intravenous, oral or rectal solutions and plain uncoated tablets are appropriate for acute therapy, while reliably absorbed slow‐release formulations offer therapeutic advantages for the management of chronic asthma, particularty in patients with rapid elimination. Dosage for long‐term therapy is determined by starting with low doses that allow virtually complete acceptance of the medication followed by gradual increases, if tolerated, at three day intervals until mean age‐specific doses are reached. Subsequent adjustment in dosage regimens are then based upon serum concentration measurements. Most clinical laboratories now measure theophylline, and newer systems have been developed to provide emergency results within minutes at a reasonable cost. In cases of theophylline poisoning, the drug must be rapidly removed to prevent life‐threatening toxicity. When serum concentrations are in excess of 60 μg/ml charcoal hemoperfusion dialysis may be indicated, even in the absence of obvious signs of toxicity.

The Relation of Product Formulation to Absorption of Oral Theophylline

To assess the potential for therapeutic problems related to the bioavailability of oral theophylline preparations, we examined the rate and extent of absorption for various formulations in adult volunteers. Absorption of theophylline from a solution or from uncoated tablets was rapid and complete. Three of six sustained-release formulations were more slowly, but still completely and consistently, absorbed. Absorption of the other three sustained-release formulations appeared to be more erratic and less complete. Serum concentration-time curves during multiple eight-hour dosing were simulated for the bioavailable preparations. With three sustained-release formulations it was predicted that fluctuations in serum theophylline concentrations between doses would decrease, as compared with uncoated tablets, to a clinically important extent, particularly in children, in whom elimination of theophylline is generally rapid.

Monitoring Serum Theophylline levels

SummaryRecent definition of the pharmacodynamics and pharmacokinetics of theophylline have increased the safety and efficacy of the drug for acute bronchodilator therapy and have greatly expanded its potential as a prophylactic agent in the management of chronic asthmatic symptoms. Specifically, benefit and risk from theophylline have been demonstrated to relate directly to serum theophylline concentration, which is itself a function of not only the dose but also the elimination characteristics of the drug in the individual patient.When used to treat acute symptoms, an initial loading dose of theophylline based on a volume of distribution of 0.5L/kg (range — 0.3 to 0.7L/kg) is required to rapidly attain maximum bronchodilator effect. There are wide interpatient differences in elimination rate. Dosage for continued therapy must be matched to the rate of elimination in the individual patient, which can be expressed as clearance. Under normal circumstances, this can only be done empirically by monitoring serum theophylline concentration at intervals and adjusting dosage until a steady state is reached with the serum theophylline concentration within the 10 to 20μg/ml therapeutic range.During long term therapy, product formulation must be carefully considered; sustained release preparations, if completely and reliably absorbed, offer therapeutic advantage, particularly for children. The most acceptable way to determine final dosage for long term therapy is to begin with doses sufficiently low to allow virtually universal acceptance of the medication, although optimum benefit will be obtained in very few. Gradual increases in dose at 3 day intervals until average doses are reached, if tolerated, minimises the frequency with which serum theophylline concentrations need to be measured. These doses should then, however, not be maintained or increased further without measurement of serum theophylline concentration. Final dosage adjustment can then be made. Serum theophylline measurement is therefore essential for optimum management of chronic asthma and, when rapidly available, increases the utility of theophylline for acute therapy.Six different basic methods for measuring theophylline in serum or plasma have been developed and multiple modifications of many of these have been utilised in various laboratories. Of greatest relevance are: (I) modifications of the traditional extraction methodology and measurement of ultraviolet absorbance first reported by Schack and Waxler in 1949; (2) high pressure liquid chromatography of which the reverse phase technology has become the most popular because of its commercial availability; and (3) the enzyme immunoassay which has recently been released and appears to have distinct advantage for the average clinical laboratory with regard to cost, specificity, ease of operation, speed of the assay and potential application of the equipment for assaying drugs other than theophylline.

A Clinical and Pharmacokinetic Basis for the Selection and Use of Slow Release Theophylline Products

SummaryIn order to achieve the greatest chance for maximum benefit from theophylline in the management of chronic asthma, the serum concentration should be maintained in the therapeutic range of 10 to 20 μg/ml. Conventional rapid release formulations produce excessive fluctuations in serum concentrations that can result in variability in clinical response between doses. In contrast, slow release formulations have the potential to achieve relatively constant serum concentrations with 12-hour dosing intervals, thus providing around-the-clock stabilisation of the hyper-reactive airways that characterise chronic asthma. Furthermore, the decreased frequency of dosing with these formulations can improve patient compliance. However, significant differences in rate and extent of absorption exist between the available formulations. Single-dose bioavailability studies comparing a slow release product with an oral solution or plain uncoated tablet in a crossover design permit examination of the rate and extent of absorption. Comparison of a slow release product with an oral reference following multiple doses at steady-state permits examination of the extent but generally not rate of absorption.The mean fraction absorbed-time profile, calculated from a modification of the Wagner-Nelson equation, is a process-independent method of comparing rates of absorption of different products after single doses. A prospective study in 14 children with chronic asthma has demonstrated that this modified equation, when rearranged to iteratively solve for serum concentrations, can accurately predict steady-state serum concentrations for different dosing intervals in patient populations with different rates of elimination. When slow release products are compared in this manner at 8- or 12-hour dosing intervals for patients with slow elimination, clinically relevant differences between brands are not apparent. However, in patients with rapid elimination, i.e. children, cigarette smokers, and 25% of non-smoking adults, application of this method shows that only some formulations (i.e. ’slo-Bid Gyrocaps’ and ‘Theo-Dur’, which is also marketed under different brand names such as ’sustaire’, ‘Pulmi-Dur’ and ‘Theolin Retard’) can maintain serum concentrations within the therapeutic range for an entire 12-hour dosing interval. More rapidly absorbed slow release products must be administered at 8-hour dosing intervals in patients with rapid elimination, despite promotional claims to the contrary. Current products promoted for once-a-day administration are clinically inadequate because of incomplete and erratic absorption, and/or excessive serum concentration fluctuations. With one of these formulations, ‘Theo-24’ (also marketed under the name ‘Pulmo-Timelets’), there is evidence that food induces dose dumping of potentially toxic amounts of the drug.The primary goal for a slow release product should be to maintain a constant serum concentration which is a function of the rate of absorption (a product variable), the rate of elimination (a patient variable), and the dosing interval (a prescribing variable). The dose of all slow release theophylline products must be slowly titrated to age-specific mean weight-adjusted levels before serum concentrations are obtained to guide final dosage adjustment.

Frequent Toxicity from IV Aminophylline Infusions in Critically Ill Patients

Use of recommended IV aminophylline dosage regimens in 48 older, acutely ill, hospitalized patients with chronic obstructive pulmonary disease (COPD) resulted in excessive plasma theophylline concentrations in 29 percent of these patients. A mean dose of 0.89 mg/kg/hr produced a plasma concentration which ranged from 7 to 52 mcg/ml with a mean of 21.9 mcg/ml. Plasma theophylline concentration was determined spectrophotometrically from plasma samples drawn at least 12 hours after a loading dose and initiation of a constant infusion. Severity of toxicity strongly correlated with the plasma theophylline concentration in 18 patients. Nausea and/or vomiting preceded life-threatening drug-induced arrhythmias and seizures less than half the time. Tachycardia was found to be the most consistent symptom associated with toxicity. These patients had lower plasma clearances than otherwise healthy younger adult asthmatics and healthy volunteers. Toxicity and identifiable risk factors for excessive plasma levels strongly correlated with reduced plasma clearance. Dosage modifications based upon plasma clearances from COPD patients without concurrent functional abnormalities and those with liver dysfunction and cardiac decompensation ranged from 0.7 to 0.12 mg/kg/hr. This study clearly demonstrates the poor correlation between dose and plasma concentration and the strong relationship between toxicity and plasma concentration. These results as well as those previously reported mandate that the relatively simple, rapid and inexpensive theophylline plasma measurement be used in all patients receiving IV aminophylline for longer than 24 hours in order to prevent toxicity.

Slow-Release Theophylline Rationale and Basis for Product Selection

The Rationale for Slow-Release Theophylline In 1974 a report of a placebo-controlled double-blind crossover study indicated that treatment with theophylline was associated with a dramatic decrease ...

Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma

Completeness of absorption and fluctuations in serum, theophylline concentration were examined in 14 children, 8 to 17 years of age (mean 12.4), with chronic asthma treated in variable sequence with a slow-release formulation at eight- and 12-hour intervals, and plain tablets every six hours. The total fraction absorbed for the slow-release formulation was 0.98 +/- 0.07 (mean +/- SEM) during the eight-hour and 0.99 +/- 0.04 during the 12-hour regimens. Observed fluctuations in 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 formulations (18 brand names) for eight- and 12-hour dosing in an average child and adult (elimination half-lives of 3.7 and 8.2 hours, respectively). Although predicted peak concentrations were less than twice the trough for all products when given at 12-hour intervals to an average nonsmoking adult, only two of the nine formulation (both from the same manufacturer) were likely to maintain predicted fluctuations within the 10 to 20 micrograms/ml therapeutic range during 12-hour dosing intervals in an average child. Most children and those adults with rapid elimination generally will require eight-hour dosing with the other products.

Oral theophylline dosage for the management of chronic asthma

Theophylline dosage requirements to maintain serum concentrations of 10 to 20 microgram/ml among asthmatic patients were examined in 156 children, ages 2 1/2 months to 16 years, and 33 otherwise health adults. Using 100% bioavailable preparations, low doses were used initially and increased, if tolerated, at three-day intervals. Final dosage was based on serum theophylline 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 beyound age 9 years to 13 mg/kg/day for patients beyoung 16 years of age. Although interpatient variability in dosage was confirmed at all 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.

In the Community

Chemoprophylaxis for the prevention of meningococcal disease is indicated only for intimate contacts, such as those who eat and sleep in the same dwelling as the index case. Polysaccharide vaccines are effective in preventing infections due to serogroup A and C meningococci in high risk groups such as military recruits and during epidemics. Sulfadiazine remains the chemoprophylactic agent of choice if the index case is known to be serogroup B or Y or sulfonamide susceptible. Rifampin is recommended when the serogroup and antimicrobial susceptibility are unknown. Minocycline may be used as an alternative to rifampin if the dose does not exceed 100 mg/M2/day. Reversible minocycline-induced vestibular toxicity appears to be related to excessive serum concentrations.

Effect of erythromycin on theophylline kinetics

The effect of erythromycin base on theophylline kinetics was studied in eight informed, nonsmoking, adult males who received a 15-min infusion of theophylline (aminophylline) 5 mg/kg, prior to (control) and after (experimental) a 7-day course of 1 gm daily erythromycin base (E-Mycin). Each subject acted as his own control. Multiple serum samples were collected for 24 hr after each dose and were analyzed for theophylline by high-pressure liquid chromatography. The mean +/- SD pharmacokinetic parameters for each phase of study were as follows: apparent volume of distribution (L/kg) 0.45 +/- 0.05 (control), 0.41 +/- 0.05 (experimental); clearance (ml . min/kg) 0.83 +/- 0.17 (control), 0.60 +/- 0.11 (experimental); elimination half-life (hr) 6.65 +/- 1.88 (control), 8.10 +/- 1.58 (experimental). Erythromycin significantly affected the elimination half-life and clearance of theophylline (p less than 0.05). The apparent volume of distribution was unaffected (p greater than 0.05). Therefore patients being administered theophylline appear to be at added risk for the development of toxicity when erythromycin is added to the therapeutic regimen.