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DRUG INTERACTIONS |
From the Clinical Pharmacology Unit (Dr Murdoch, Mr Zussman, Dr Schofield) and Biostatistics and Datasciences (Ms Webber), GlaxoSmithKline, Harlow, United Kingdom.
Address for reprints: R. D. Murdoch, PhD, Clinical Pharmacology Unit, GlaxoSmithKline, New Frontiers Science Park, Third Ave, Harlow, UK.
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ABSTRACT |
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 TOP ABSTRACT STUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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) was found to be similar in both smokers and nonsmokers (8.47 ± 2.20 µg•h/mL and 7.70 ± 2.25 µg•h/mL, respectively). Throughout all three studies, cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitors, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate cilomilast from theophylline for drug-drug liability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.
Key Words: Cilomilast • theophylline • smokers and nonsmokers • pharmacokinetics • drug interactions
The PDE4 enzyme plays a major role in modulating the activity of cyclic AMP (cAMP), an important secondary messenger that suppresses inflammatory cell function and mediates the relaxation of airway smooth muscle, thereby attenuating the inflammatory response.2 Selective PDE4 inhibitors block the hydrolysis of cAMP and are an attractive target for novel anti-inflammatory drugs.3 Cilomilast has been shown to exert potent anti-inflammatory effects, making it a promising candidate as a therapeutic intervention in COPD.4,5
Theophylline, a nonselective PDE inhibitor, has been used in the treatment of COPD for many years. However, its use presents many clinical limitations. Theophylline has a narrow therapeutic margin, and the dose must be carefully titrated with routine blood monitoring to avoid the occurrence of plasma concentration-related adverse effects.6 Approximately, 10% to 15% of patients receiving theophylline experience gastrointestinal upset, insomnia, and other minor side effects.7 However, potentially dangerous cardiovascular and central nervous system complications, such as arrhythmias and convulsions, can occur when theophylline plasma levels rise above 20 µg/mL.8 Due to these tolerability issues, the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines on the management of COPD have positioned the recommended use of theophylline as restricted to poorly controlled individuals with more severe disease.9
The use of theophylline is further complicated by potential drug interactions. Theophylline is predominantly metabolized by the cytochrome P450 enzyme, CYP1A2, and interacts with many drugs and compounds that inhibit this enzyme, including ß2-agonists, antibiotics, oral contraceptives, digoxin, warfarin, and tobacco smoke.10,11 Given the multicomponent nature of COPD, multiple pharmacological therapies are likely to be required to treat the disease, and the potential for drug-drug interactions is, therefore, an important consideration.12
Constituents of tobacco smoke, such as benzo[a]pyrene, are well-characterized inducers of drug-metabolizing enzymes—mainly, CYP1A1 and CYP1A2.13 Consequently, the clearance rate of drugs metabolized by these enzymes may be increased, leading to a reduction in drug efficacy. Indeed, smokers have been shown to require higher doses of theophylline to compensate for the significant increase in clearance caused by this phenomenon. This is an important consideration in the posology of certain narrow therapeutic index drugs.
Cilomilast is metabolized by several enzymic pathways operating in parallel, of which the most important oxidative pathway is mediated by CYP2C8. Cilomilast would, therefore, be expected to have a low potential for drug interactions.
To confirm these hypotheses, three separate pharmacokinetic studies exploring the drug interaction potential of cilomilast were conducted. Of these, two studies investigated the interaction of theophylline and cilomilast in healthy volunteers. These studies were undertaken to establish the feasibility of switching individuals from theophylline to cilomilast regimens within single-dosing intervals and to ascertain the tolerability following coadministration of both agents. It was not envisaged that there would be any metabolic interactions between theophylline and cilomilast due to their different routes of metabolism and multiplicity of pathways. The third study examined the effect of smoking on the pharmacokinetic profile of cilomilast. Similarly, no difference in the therapeutic effect of cilomilast based on tobacco use was expected.
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STUDY DESIGN |
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TOPABSTRACTSTUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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These studies were carried out at a single center (PAREXEL, Berlin, Germany) and conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki (as amended, 1996). All volunteers provided written consent.
For the coadministration studies, the major inclusion criteria were that subjects were male, between ages 18 and 50 years, and nonsmoking. They had a body weight of 50 kg, had no abnormality on clinical examination, and screened negative for hepatitis B and C and HIV-1/2. Subjects were excluded if they refused to abstain from alcohol and exercise for 24 hours prior to and following each study session, had a history of intolerance to theophylline or caffeine-like agents, or had a history or presence of gastrointestinal, hepatic, or renal disease. Subjects who had received over-the-counter or prescribed medication within 7 days before the first study day that could have interfered with the study procedures or compromised safety were not permitted to enter the study.
For the smoking study, the main inclusion and exclusion criteria were the same for the coadministration studies, apart from the fact that smokers had to have a history of 20 or more cigarettes/day for at least 6 months and a plasma cotinine level of > 200 ng/mL at screening and before dosing. Nonsmokers had to be lifelong nonsmokers, not regularly exposed to passive smoking, and to have plasma cotinine levels < 100 ng/mL.
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ESCALATING THEOPHYLLINE DOSE STUDY |
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TOPABSTRACTSTUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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PRETITRATED THEOPHYLLINE CONCENTRATION STUDY |
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TOPABSTRACTSTUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Regimen A: cilomilast coadministered with individualized theophylline
Regimen B: cilomilast coadministered with theophylline placebo
Regimen C: individualized theophylline coadministered with cilomilast placebo
Regimen D: theophylline placebo coadministered with cilomilast placebo
Each dosing session was separated by washout periods of at least 7 days. Safety and pharmacokinetic assessments were carried out during the 4-day dosing session. Subjects were dosed in the fed state during all four arms of the crossover and during the individualization phase.
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EFFECT-OF-SMOKING STUDY |
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TOPABSTRACTSTUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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20 cigarettes/day) and 13 nonsmokers, were included in the study. Subjects were ages 18 to 65 years, and smokers and nonsmokers were matched for age (±5 years) and body weight (±5 kg), with the exception of 1 nonsmoker who could not be matched. Each subject received a single 15-mg oral dose of cilomilast in the fasted state. |
METHODS |
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In the pretitrated theophylline concentration study, pairs of blood samples (1 x 2.5 mL into EDTA-containing tubes and 1 x 3 mL into heparin tubes) were collected on days 2 and 3 at pre-morning and pre-evening doses, as well as on day 4 at the pre-morning dose and at 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose for the determination of cilomilast and theophylline concentrations and pharmacokinetic profiles.
Similarly, in the effect-of-smoking study, blood samples (2.5 mL) were collected into EDTA-containing tubes predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 hours after dosing for the determination of cilomilast plasma concentrations and pharmacokinetic profiles.
In all studies, plasma concentrations of cilomilast were determined using protein precipitation with toluene, acetonitrile, or methanol followed by liquid chromatography tandem mass spectrometry (LC/MS/MS) analysis employing the negative-ion turbo ionspray ionization method. The lower limit of quantification (LLQ) for cilomilast based on a 100-µL aliquot was 0.010 µg/mL. In the theophylline coadministration studies, plasma concentrations of theophylline were determined by using a method based on solvent extraction with isopropyl alcohol followed by high-performance liquid chromatography (HPLC) analysis with UV absorbance detection. The LLQ for theophylline was 0.05 µg/mL for a 500-µL aliquot.
For each drug, plasma concentration-time data were analyzed by the noncompartmental pharmacokinetic analysis program WinNonlin Professional (version 2.1; Scientific Consulting Inc., Cary, NC). The maximum plasma concentration (Cmax) and the time taken to reach Cmax (tmax) were obtained by visual inspection of the individual plasma concentration-time profiles for the occurrence of peak plasma concentrations. The total area under the plasma concentration-time curve from time 0 to the last quantifiable time point (AUC0-12) or (AUC0-) was estimated by a combination of linear and logarithmic trapezoidal methods over increasing and decreasing plasma concentrations, respectively.
Safety Assessment
In each study, supine and erect vital signs (blood pressure and pulse), as well as 12-lead and Holter ECGs, were measured predose and at regular intervals postdose. Samples for the measurement of hematology and clinical chemistry were taken predose, at regular intervals postdose, and at follow-up. Adverse clinical effects were monitored throughout each study.
Statistical Methods
In the escalating theophylline dose study, no formal statistical analyses were performed. Data were summarized by regimen and theophylline dose.
In the pretitrated theophylline concentration study, following loge transformation, steady-state AUC0-12 and Cmax of theophylline on day 4 of the crossover phase were analyzed by analysis of covariance, fitting a model with terms for sequence, subject (sequence), period, and regimen (data from regimens A and C only). The residual variance from the model was used to calculate 90% confidence intervals (CIs) for the differences between the regimens on the loge scale. These were back-transformed to give point estimates and 90% CIs for the ratio (cilomilast + theophylline):(placebo + theophylline). Steady-state AUC0-12 and Cmax of cilomilast on day 4 were also analyzed as described above, but 95% CIs were derived for all cilomilast parameters (data from regimens A and B only). Steady-state tmax of cilomilast and theophylline were analyzed nonparametrically separately using Wilcoxon matched pairs, and the median difference was calculated with a 95% CI.
In the effect-of-smoking study, smokers and nonsmokers were compared by separate one-way analysis of variance with respect to AUC0- and Cmax. These parameters were log-transformed (to base e) prior to analysis. The ratios of smokers to nonsmokers for AUC0- and Cmax were estimated with 90% CIs; t1/2 was analyzed untransformed, and a 95% CI for the difference (smokers - nonsmokers) was calculated. The tmax was analyzed using the Wilcoxon two-sample method (Mann-Whitney U test), and a 95% CI for the median difference (smokers - nonsmokers) was calculated.
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RESULTS |
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Pharmacokinetic Profile of Cilomilast
The steady-state pharmacokinetics of cilomilast were not affected by the concomitant administration of single, increasing oral doses of theophylline (60-240 mg; Figure 1a). No notable differences were revealed in cilomilast mean plasma concentrations following concomitant administration with a pretitrated therapeutic dose of theophylline or placebo (Figure 1b).
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Maximal plasma concentrations of cilomilast were observed between 1 and 4 hours following administration of cilomilast either in combination with a pretitrated therapeutic dose of theophylline (regimen A) or with placebo (regimen B) (Table I).
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Slight increases of 3% and 6% were noted in cilomilast pharmacokinetic parameters—Cmax and AUC0-12, respectively—following coadministration with a pretitrated therapeutic dose of theophylline (regimen A) compared to cilomilast dosed with placebo (regimen B). The 95% CI indicated that the true increase is unlikely to be greater than 20% for Cmax and 12% for AUC0-12 (Table I).
Pharmacokinetic Profile of Theophylline
On examining the steady-state pharmacokinetic profile of theophylline, no notable differences were revealed in theophylline mean plasma concentrations following concomitant administration with cilomilast or placebo (Figure 2).
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Maximal plasma concentrations of theophylline were generally observed between 0 and 6 hours following administration of a pretitrated therapeutic dose of theophylline either in combination with cilomilast (regimen A) or placebo (regimen C) (Table II).
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Individuals receiving a pretitrated therapeutic dose of theophylline coadministered with cilomilast (regimen A) revealed no notable effects on theophylline Cmax and AUC0-12 when compared to those receiving theophylline and placebo (regimen C). The point estimate and 90% CIs for theophylline Cmax and AUC0-12 were completely contained within the specified interval for equivalence (0.8-1.25), indicating a lack of effect of coadministrating cilomilast on the pharmacokinetics of theophylline (Table II).
Similarly, in the escalating dose study, no notable differences were seen in mean plasma concentration-time plots or pharmacokinetic parameters of theophylline following coadministration with cilomilast (not shown).
Pharmacokinetics of Cilomilast in Smokers and Nonsmokers
On comparing the pharmacokinetic profile of cilomilast between smokers and nonsmokers, no clinically important differences were observed (Table III). Cilomilast appeared in the plasma of all subjects in both groups within 30 minutes of dosing. Peak concentrations were usually achieved within 1 to 3 hours and were followed by a steady, essentially monophasic, decline (Figure 3).
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On average, values of AUC0- and Cmax were approximately 10% and 19% lower, respectively, in smokers compared with nonsmokers (Table III). The 90% CI for AUC0- fell within the pretitrated equivalence range (0.70-1.43), indicating a lack of effect of smoking on cilomilast exposure. The 90% CI for Cmax extended marginally below the lower end of this interval; however, this is unlikely to be of any clinical significance in the absence of any change in overall exposure of the drug.
The half-life (t1/2) of cilomilast was similar in smokers and nonsmokers (Table III). Taken together with AUC0-, no important differences in the clearance of cilomilast due to smoking were noted.
Safety and Tolerability
Cilomilast at both 10-mg and 15-mg doses were generally well tolerated in both the theophylline coadministration studies. The most frequently reported adverse events (AEs) following concurrent treatment were headache (n = 3, 10 mg), dizziness (n = 2, 10 mg; n = 1, 15 mg), and gastrointestinal disturbances, such as nausea (n =1,10mg),dyspepsia (n =2, 10 mg; n = 2, 15 mg), and vomiting (n = 1, 10 mg). Cilomilast was also well tolerated by both smokers and nonsmokers. The most frequently reported AE by smokers was headache (n = 6), while in the nonsmoking subjects, nausea was most frequently reported (n = 5). All AEs throughout the three studies were of mild to moderate intensity and had resolved by the end of the study.
Cilomilast was not associated with clinically relevant changes in cardiac function, ECG, routine clinical chemistry, hematology, and urinalysis. No serious adverse events or deaths occurred during any of the studies.
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DISCUSSION |
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TOPABSTRACTSTUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In contrast to theophylline, the selective PDE4 inhibitor, cilomilast, is metabolized by a multiplicity of pathways and is therefore expected to have a low potential for drug interactions. Indeed, the studies reported here present no evidence of a clinically significant interaction between cilomilast and theophylline when the two agents were coadministered in healthy volunteers. The absence of any adverse drug-drug interaction between cilomilast and theophylline supports earlier findings demonstrating a lack of drug-drug interaction potential of cilomilast when coadministered with other commonly prescribed drugs in COPD, such as salbutamol,14 digoxin,15 and warfarin.16
The coadministration studies also served to highlight the ability to switch patients from theophylline to cilomilast-containing regimens in a single dosing regimen, without a need for a washout period, as the pharmacokinetic profile of cilomilast was unaffected by theophylline coadministration. This highlights the benefit for those individuals who appear intolerant to the effects of theophylline to be switched to cilomilast, which has a more favorable prescribing profile. Moreover, therapeutic levels of theophylline have been shown to induce marked pharmacodynamic alterations, such as an increase in heart rate and arrhythmias, whereas cilomilast has no significant effect on the cardiovascular system.14
Although such prescribing would be highly unlikely in a clinical setting, the hypothetical risk for increased gastrointestinal adverse events following coadministration of theophylline and cilomilast was not observed.
Smoking accounts for 80% to 90% of COPD cases.17 These patients either continue to smoke or take at least several attempts before quitting successfully. These quitting and relapsing episodes are a reality in the clinical setting,18 and drugs used for the treatment of COPD are, therefore, often likely to be administered to patients who are smokers. This is of particular concern when prescribing drugs that are known to be affected by constituents of tobacco smoke.
Pharmacokinetic studies of theophylline have demonstrated that cigarette smoke is a major determinant of the variability in theophylline disposition and that smokers may require daily dosages of theophylline twice those needed by nonsmokers.19 Dose adjustments through routine blood monitoring are, therefore, necessary to ensure that therapeutic levels of theophylline are achieved. Although this aspect of prescribing is instrumental to the safety and efficacy of theophylline, some practitioners surveyed did not check theophylline levels either at the start of treatment or during long-term treatment,20 possibly due to lack of health care resources. The clinically insignificant effect of smoking on cilomilast clearance contrasts with the clinically relevant effect of smoking on theophylline and demonstrates that no dose adjustment is required in smokers on cilomilast. Therefore, cilomilast may be administered to COPD patients who are at different stages of the quit attempt or to those who have relapsed, without undue clinical concern.
In summary, data from these studies demonstrate a lack of a clinically important effect of cilomilast on the pharmacokinetics of theophylline and vice versa. These data also demonstrate the feasibility of switching patients from theophylline to cilomilast or coadministrating both, without raising significant safety and tolerability issues. Smoking had little effect on the pharmacokinetic profile of cilomilast, indicating an absence of a dose adjustment requirement in smokers. Taken together with previously published data on the lack of interaction of cilomilast with digoxin, warfarin, and salbutamol, this clearly differentiates cilomilast from theophylline as a pharmacological intervention in COPD.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSTUDY DESIGNESCALATING THEOPHYLLINE DOSE...PRETITRATED THEOPHYLLINE...EFFECT-OF-SMOKING STUDYMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication December 6, 2003; Revised version accepted March 22, 2004.
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REFERENCES |
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