Achieving the World Health Organization's vision for clinical pharmacology.

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence-based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co-morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need.

Research tasks as part of the general practice clerkship in undergraduate medical education - a pilot project on feasibility and acceptance.

OBJECTIVE: To assess the integration of a research task performed by students during their two-week clerkship in general practice. METHODS: Students were assigned to interview five patients with coronary heart disease using a standardised questionnaire focusing on potential interaction of medications with statins. Acceptance and feasibility was assessed by means of a questionnaire survey of teaching physicians (n = 20) and students (n = 20). RESULTS: According to most teaching physicians and students the recruitment of patients during the two-week clerkship was possible, and the practice work flow was not disturbed by the project. Both groups considered the research task on the documentation of potential drug interactions with statins as suitable. According to the teaching physicians the project had a learning effect for the students. In contrast, the students graded their learning effect less highly between 'satisfactory' and 'sufficient'. The overall assessment of the project by the students was on average 'satisfactory' and differed from the assessment by the teaching physicians ('good'). CONCLUSIONS: Adequate informing of students and participating physicians about the nature of the project and presenting preliminary results of the data in a plenary session at the end of the clerkship are essential for the acceptance of such projects.

Mechanisms and assessment of statin-related muscular adverse effects.

Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.

Statin use and its association with musculoskeletal symptoms--a cross-sectional study in primary care settings.

INTRODUCTION: Musculoskeletal complaints are very common in primary care settings. Lipid-lowering drugs are one of several causes of musculoskeletal symptoms. However, data showing an association of lipid-lowering drug therapy and increased odds of musculoskeletal complaints in primary care patients are lacking. OBJECTIVE: To investigate the association between statin use and the reporting of muscular complaints by patients and simultaneously control for several known factors of musculoskeletal complaints. METHODS: In a cross-sectional study with 1031 consecutive patients (>50 years of age) in 26 offices of GPs, two investigators collected the data from the office files and by interviewing the patients. A logistic regression model was used to identify variables affecting the odds of muscular symptoms. RESULTS: The prevalence of lipid-lowering drug prescription was 23% (n = 239) and that of muscular complaints was 40% (n = 411). In all, 44% (n = 106) of the patients with lipid-lowering drug prescription had muscular complaints compared to 39% (n = 305) of the patients without lipid-lowering drug therapy. Statin prescription and 10 variables remained in the final model. Statin prescription is associated with a 1.5-fold odds of musculoskeletal complaints compared to non-prescription {odds ratio [OR] = 1.5 [95% confidence interval (CI), 1.1-2.0], P = 0.02}. CONCLUSION: Having a statin prescription appears to be an independent factor associated with musculoskeletal symptoms in primary care settings. Statin use may be more often associated with musculoskeletal complaints than previously assumed.

Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists.

The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.

Chronic Heart Failure.

BACKGROUND: Chronic heart failure (CHF) is the most common reason for hospital admissions in Germany. For the National Disease Management Guideline (NDMG) on CHF, a multidisciplinary expert panel revised the chapters on drug therapy, invasive therapy, and care coordination, following the methods of evidence-based medicine. METHODS: Recommendations are based on international guideline adaptations or systematic literature search. They were developed by a multidisciplinary expert panel, approved in a formal consensus procedure, and tested in open consultation, as specified by the requirements for S3 guidelines. RESULTS: The pharmacological treatment is based on ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists as well as diuretics to treat fluid retention, if present. Sacubitril/Valsartan and ivabradine showed positive effects on mortality in large but methodologically limited RCT. They are recommended if established combination therapy is not sufficient for symptom control, or if drugs are not tolerated/contraindicated. The indications for pacemakers or defibrillators have been confined to patient subgroups in which clinical trials have shown a clear benefit. Moreover, the goals of treatment and the patient's expectations should be aligned with each other. Structured care programs, specialized nurses, remote, or telephone monitoring showed moderate effects on patient related outcomes in RCT. CONCLUSION: All patients with heart failure are suggested to be enrolled in a structured program (e.g., a disease management program) including coordinated multidisciplinary care and continuous educational interventions. In patients with a poor prognosis, more intensive care is recommended, e.g. specialized nurses, or telephone support.

Effect of high-dose metronidazole on pharmacokinetics of oral budesonide and vice versa: a double drug interaction study.

Recent case reports suggest that addition of high-dose metronidazole might be associated with elevated plasma concentrations of substrates of cytochrome P450 (CYP) 3A. Because patients with fistulizing Crohn's disease benefit by using high doses of metronidazole for prolonged periods, this study's primary aim was to evaluate the effect of high-dose metronidazole on the pharmacokinetics of oral budesonide, a sensitive substrate of CYP3A commonly prescribed in acute inflammatory bowel disease. Twelve healthy adults received 1.5 g metronidazole per day over 1 week. The CYP3A-dependent metabolic profile of an oral dose of budesonide (3 mg) and that of endogenous cortisol were compared intraindividually before and after administration of metronidazole. There was neither a significant effect of high-dose metronidazole on the area under the plasma concentration-time curve (AUC) of budesonide (90% confidence interval, 79%-115%) nor on the AUC ratios of 6beta-hydroxybudesonide/budesonide and 16alpha-hydroxyprednisolone/budesonide. In parallel, metronidazole did not significantly alter formation of 6beta-hydroxycortisol. Vice versa, budesonide did not affect the AUC of metronidazole (90% confidence interval, 91%-100%). The authors conclude that in contrast to concomitant intake of other imidazoles such as ketoconazole, concomitant intake of metronidazole may not lead to serious safety concerns due to elevated systemic concentrations of the glucocorticoid budesonide.

Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.

The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 microg once daily was well tolerated.

Polypharmacy-an Upward Trend with Unpredictable Effects.

BACKGROUND: Guideline-oriented treatments can lead to polypharmacy, i.e., the simultaneous long-term use of multiple drugs. Polypharmacy mainly affects elderly patients. The goal of this review is to survey the current scientific evidence about polypharmacy, focusing on clinical endpoints, and to point out implications for medical practice and research. METHODS: This selective literature review is based on pertinent publications that were retrieved by a selective search in PubMed employing the terms "polypharmacy AND general practice." Selected references were considered as well. RESULTS: In Germany, polypharmacy currently affects approximately 42% of persons over age 65, with an ongoing upward trend. 20-25% of these patients receive potentially inappropriate drugs. Approximately 86% of the daily doses of drugs taken by persons over age 65 are prescribed by general practitioners. There is inconsistent evidence on the question whether polypharmacy affects clinical endpoints such as mortality. It cannot be determined with certainty whether polypharmacy itself, or the underlying multimorbidity, is the reason for worse clinical outcomes. Lists, instruments, and guidelines such as PRISCUS (a list of potentially inappropriate drugs for elderly patients), FORTA (Fit fOR The Aged), MAI (the Medication Appropriateness Index), and the Hausärztliche Leitlinie Multimedikation (a German-language guideline on polypharmacy for general practitioners) can help physicians take care of patients who are taking multiple drugs. It has not yet been proven, however, that their use has any effect on clinical outcomes. CONCLUSION: The decision whether to keep giving a drug or to discontinue it must always be made individually on the basis of current treatment goals; drug lists and a pertinent general practitioners' guideline can be useful aids in decision-making. Efforts to pay more attention to multimorbidity and polypharmacy in future studies and guidelines are deserving of support.

Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study.

OBJECTIVE: Our objective was to study the impact of the cytochrome P450 (CYP) 2D6 polymorphism on the tolerability of metoprolol in a real-life primary care setting. The adverse effects studied comprised effects related to the central nervous system, cardiovascular effects, and sexual dysfunction. METHODS: Patients in whom treatment with metoprolol was considered were enrolled into this prospective, 6-week multicenter study. The dosage of metoprolol was determined on an individual basis and could be freely adjusted on clinical grounds. The indication for treatment was hypertension in about 90% of cases. Systolic and diastolic blood pressure, resting heart rate, and plasma metoprolol and alpha-hydroxymetoprolol concentrations were measured. CYP2D6 genotyping covered alleles *3 to *10 and *41 and the duplications. Possible adverse effects of metoprolol were systematically assessed over a 6-week period by means of standardized rating scales and questionnaires. RESULTS: The final study population comprised 121 evaluable patients (all white patients); among them, there were 5 ultrarapid metabolizers (UMs) (4.1%), 91 extensive metabolizers (EMs) (75%), 21 intermediate metabolizers (IMs) (17%), and 4 poor metabolizers (PMs) (3.3%). Plasma metoprolol concentrations normalized for the daily dose and metoprolol/alpha-hydroxymetoprolol ratios at steady state were markedly influenced by CYP2D6 genotype and displayed a gene-dose effect. The median of the dose-normalized metoprolol concentration was 0.0088 ng/mL, 0.047 ng/mL, 0.34 ng/mL, and 1.34 ng/mL among UMs, EMs, IMs, and PMs, respectively (P<.0001). There was no significant association between CYP2D6 genotype-derived phenotype (EMs and UMs combined versus PMs and IMs combined) and adverse effects during treatment with metoprolol. There was a tendency toward a more frequent occurrence of cold extremities in the PM plus IM group as compared with the EM plus UM group (16.0% versus 4.2%, P=.056; relative risk, 3.8 [95% confidence interval, 1.03--14.3]). CONCLUSIONS: CYP2D6 genotype-derived phenotype was not significantly associated with a propensity for adverse effects to develop during treatment with metoprolol. However, the results concerning tolerability of metoprolol in PMs were inconclusive because of the small number of PMs enrolled.

Using trade names: a risk factor for accidental drug overdose.

Medication errors due to the exclusive use of trade names of drugs may lead to life-threatening complications. We report the case of a patient with verapamil overdose as a result of this. This case illustrates that the use of trade names, omitting the international nonproprietary names of the active moiety, carries the risk of serious adverse drug events by overdose.

Visual disorders associated with omeprazole and their relation to CYP2C19 polymorphism.

Risk factors for patients developing visual disturbances in association with proton pump inhibitors are unknown. As omeprazole is substantially metabolized by polymorphic CYP2C19, we retrospectively identified and genotyped patients who experienced this adverse reaction. Among 29 patients, we found two poor metabolizers (PMs) of CYP2C19. The PM genotype does not appear to be a risk factor for omeprazole-associated visual disorders.

Clinical pharmacokinetics of candesartan.

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II type 1 (AT1) receptor antagonist. Absorbed candesartan cilexetil is completely metabolised to candesartan. Oral bioavailability is low (about 40%) because of incomplete absorption. Plasma protein binding in humans is more than 99%. The volume of distribution in healthy individuals is 0.13 L/kg. CV-15959 is the inactive metabolite of candesartan. Candesartan that reaches the systemic circulation is mainly cleared by the kidneys, and to a smaller extent by the biliary or intestinal route. The apparent oral clearance of candesartan is 0.25 L/h/kg after a single dose in healthy individuals. Oral clearance (3.4 to 28.4 L/h) is highly variable among patients. No relevant pharmacokinetic drug-food or drug-drug interactions are known. The terminal elimination half-life remains unclear, but appears to be longer than the currently used range of 4 to 9 hours. Non-compartmental models do not appear to be appropriate for the analysis of candesartan pharmacokinetic data. A 2-compartment analysis revealed a much longer half-life of 29 hours using data from patients with hypertension. However, a further indepth analysis has never been performed. The concentration-effect relationship is unaffected by age. No gender or race differences have been shown in the effect or pharmacokinetics of candesartan. Renal function affects the pharmacokinetic profile of candesartan. For patients with creatinine clearances of >60 ml/min x 1.73m(2), 30 to 60 ml/min x 1.73m(2) and 15 to 30 ml/min x 1.73m(2), the elimination half-life is 7.1, 10.0 and 15.7 hours, respectively, at a dose of 8 mg/day. However, at 12 mg/day an accumulation factor of 1.71 was found. Thus, a maximum daily dose of up to 8mg appears suitable in patients with severe renal dysfunction. No significant elimination of candesartan occurs with haemodialysis. In patients with mild to moderate hepatic impairment, no relevant pharmacokinetic alterations have been observed. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease. Clinically effective dosages range between 8 and 32 mg/day. The response rate of monotherapy with candesartan in patients with hypertension increases with dosage, but never exceeds 60% at a daily dosage of 16mg of candesartan. Dosages up to 32 mg/day do not increase this response rate.

[Rationale and methods of the UNAMET study (dose- and CYP2D6-genotype-dependent adverse drug reactions of metoprolol)--a contribution to quality improvement in pharmacotherapy]. / Rationale und Methodik der UNAMET-studie (Unerwünschte Arzneimittelwirkungen von Metoprolol in Abhängigkeit von Dosis und CYP2D6-Genotyp)--ein Beitrag zur Qualitäts- verbesserung in der Pharmakotherapie.

Metoprolol has not yet been systematically studied in terms of quality of life and incidence of adverse drug reactions (ADRs). Metoprolol is metabolized by polymorphic CYP2D6, therefore poor CYP2D6 metabolizers may be at higher risk of ADRs. Therefore, it is to be proven whether genotyping is useful to guide initial dose selection. In the ongoing UNAMET study, nonrandomized out-patients start treatment with metoprolol for various disorders. With the use of standard questionnaires, the patients are prospectively evaluated for common ADRs (headache, dizziness, tiredness, sleep disturbances, dyspnea, cold extremities, sexual dysfunction) and quality of life. The questionnaires are filled out before and until 6 weeks after initiating therapy; blood pressure and heart rate are also measured. The acquired data are then related to the patients' metoprolol dose and plasma concentrations, as well as to their metabolic ratio of metoprolol/alpha-OH-metoprolol and CYP2D6 genotype.

[Quality of antithrombotic therapy in patients with chronic atrial fibrillation: the AFib Trial]. / Qualität der antithrombotischen Therapie bei chronischem Vorhofflimmern: AFib-Studie.

BACKGROUND: Large randomised studies have definitely shown that oral anticoagulation effectively reduces thromboembolic complications, e.g. stroke, in patients with chronic non-valvular atrial fibrillation (AFib). However, less than 50% of the eligible AFib patients receive anticoagulation, although their risk of thromboembolic disease is increased 5-7 fold as compared to individuals who have a regular sinus rhythm. This is the reason why undertreatment needs to be evaluated and addressed. In Germany, data on the antithrombotic therapy of these patients are sparse, national guidelines are lacking. AIM OF THE STUDY: This prospective cohort study is the first one to evaluate the quality of antithrombotic prevention in two groups of AFib outpatients in two different, socio-demographically comparable regions of Germany (Südbaden and Südwürttemberg) over a period of several years. Quality of care is defined as the percentage of AFib patients in a certain region treated according to international guidelines. If the percentage in both cohorts does not exceed 80%, guidelines are to be developed and implemented in Südwürttemberg on consideration of the specific treatment conditions in this region; their applicability is to be evaluated later. METHODS: Office-based specialists of internal and general medicine are currently recruiting 200 AFib patients in each study region for documentation of their clinical data. Besides the quality of antithrombotic chemoprevention, relevant problems emerging in antithrombotic therapy in an ambulant setting will be identified. In the area of intervention (Südwürttemberg) experts and office-based physicians will exclusively develop evidence-based guidelines and disseminate them among doctors. Six months after the implementation of these guidelines in Südwürttemberg, their influence on prescribing patterns will be determined by comparing the proportion of anticoagulated AFib patients in Südwürttemberg to that of the control cohort (Südbaden). In addition, secondary outcomes of interest include deaths, days of hospitalisation, and incidence of stroke or bleeding episodes for different antithrombotic treatments.

[Rare cause for severe hypertriglyceridemia - case 9/2013]. / Seltene Ursache einer schweren Hypertriglyzeridämie - Fall 9/2013.

HISTORY AND ADMISSION FINDINGS: We report on a 48-year-old female patient with recently developed severe hypertriglyceridemia. Medical history was remarkable for breast cancer with breast-preserving surgery and chemoradiotherapy. The patient has been treated with 20 mg tamoxifen per day for three months. INVESTIGATIONS: Laboratory results showed hypertriglyeridemia, hypercholesterolemia and lowered HDL-cholesterol. DIAGNOSIS, TREATMENT AND COURSE: Findings were consistent with a drug-induced hypertriglyceridemia caused by anti-estrogenic therapy with tamoxifen. After consulting the patient's gynaecologist, we discontinued tamoxifen treatment. Thereupon, triglyceride levels fell consistently. There were no signs of pancreatitis, serum amylase and lipase were in the normal range. CONCLUSIONS: Patients with pre-diagnosed metabolic disorders, especially dyslipidemia and type 2 diabetes, should undergo regular controls of serum triglycerides during tamoxifen treatment. Also, one should keep in mind that a subacute, severe rise in serum triglyceride levels may be caused, in rare cases, by tamoxifen treatment.

[Difficulties in adressing purging behaviour in the treatment of a patient with anorexia nervosa]. / Purging-Verhalten einer Anorexiepatientin: eine besondere Herausforderung.

HISTORY AND CLINICAL FINDINGS: We report on a 24-year-old patient with secondary amenorrhoea, underweight (BMI 15,0 kg/m²), and a fear of weight gain, who used laxatives, diuretics, excessive sport and human chorionic gonadotropin (hCG) for weight regulation. EXAMINATIONS: On physical examination, cachexia, bradycardia, lanugo hair on face and back, and cyanosis of hands and feet were observed. In the laboratory findings, leukopenia, recurrent low potassium and an elevated mean corpuscular volume (MCV) were remarkable. DIAGNOSIS, TREATMENT AND COURSE: We diagnosed anorexia nervosa, binge/purging type (AN-BP). We treated the patient for seven weeks in a multimodal setting specific for patients with eating disorders. She gained 3.9 kg (11% of her initial weight). Special challenges included the complications of her laxative abuse as well as her distinct body image disturbance. With knowledge of her background, we understood this misuse of hCG. CONCLUSION: Purging behaviour should be questioned in detail in patients with eating disorders, because purging methods are not always reported right away and are accompanied with great shame. However, purging behaviour can be very dangerous to one's health. Using a hCG diet (Hollywood diet) is a rare purging method in patients with anorexia nervosa.

Quantifying the effect of covariates on concentrations and effects of steady-state phenprocoumon using a population pharmacokinetic/pharmacodynamic model.

BACKGROUND AND OBJECTIVES: The oral anticoagulant phenprocoumon, similar to other vitamin K antagonists, is characterized by pronounced interindividual variability in the doses needed to achieve the desired therapeutic effect. Previous studies assessed the effect of genetic and demographic covariates on empirical dose requirements of phenprocoumon to enable individualized dose prediction. The aim of the present study was to quantify major sources of interindividual variability separately on the pharmacokinetics and pharmacodynamics of phenprocoumon using a population pharmacokinetic-pharmacodynamic model. METHODS: A single steady-state blood sample was collected from 278 patients and assayed by liquid chromatography-tandem mass spectrometry for phenprocoumon and its metabolites. Genotyping was performed for variants of the cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genes. Effects were quantified by international normalized ratio (INR). Data were analyzed simultaneously using NONMEM VII. RESULTS: The model confirmed CYP2C9 and VKORC1 variants as the major predictors of variability in phenprocoumon concentrations and effects, together with body weight, age, comedication with CYP3A modifiers (i.e. inhibitors or inducers) and presence of atrial fibrillation. These covariates explained 50.0 % of the observed variability in the model parameters. Phenprocoumon clearance fractions mediated per CYP2C9 allele were 13.4, 9.5 and 5.7 mL/h for the 1, 2 and 3 variants, respectively. An additional clearance fraction of 5.3 mL/h was independent of CYP2C9 activity. Homozygous VKORC1 wild-type carriers were estimated to have a 2.13-fold higher phenprocoumon exposure requirement than homozygous 1173 C>T carriers to achieve the same effect on INR. CONCLUSIONS: The model provides a deeper insight in the separate pharmacokinetic and pharmacodynamic parts of phenprocoumon action. Thus, it provides important information for individualized dose prediction, with the option to include further covariates not studied here with known effects on individual pharmacokinetic or pharmacodynamic processes.

No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: an investigation using cimetidine.

This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N-oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of roflumilast and roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of roflumilast increased by about 46%, with no effect on C(max) of roflumilast N-oxide. The increase in tPDE4i of roflumilast and roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.