A comparison of Bayesian information borrowing methods in basket trials and a novel proposal of modified exchangeability-nonexchangeability method.

Recent innovation in trial design to improve study efficiency has led to the development of basket trials in which a single therapeutic treatment is tested on several patient populations, each of which forms a basket. In a common setting, patients across all baskets share a genetic marker and as such, an assumption can be made that all patients may have a homogeneous response to treatments. Bayesian information borrowing procedures utilize this assumption to draw on information regarding the response in one basket when estimating the response rate in others. This can improve power and precision of estimates particularly in the presence of small sample sizes, however, can come at a cost of biased estimates and an inflation of error rates, bringing into question validity of trial conclusions. We review and compare the performance of several Bayesian borrowing methods, namely: the Bayesian hierarchical model (BHM), calibrated Bayesian hierarchical model (CBHM), exchangeability-nonexchangeability (EXNEX) model and a Bayesian model averaging procedure. A generalization of the CBHM is made to account for unequal sample sizes across baskets. We also propose a modification of the EXNEX model that allows for better control of a type I error. The proposed method uses a data-driven approach to account for the homogeneity of the response data, measured through Hellinger distances. Through an extensive simulation study motivated by a real basket trial, for both equal and unequal sample sizes across baskets, we show that in the presence of a basket with a heterogeneous response, unlike the other methods discussed, this model can control type I error rates to a nominal level whilst yielding improved power.

Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study.

BACKGROUND: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. RESULTS: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONS: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. TRIAL REGISTRATION: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).

SPIRIT and CONSORT extensions for early phase dose-finding clinical trials: the DEFINE (DosE-FIndiNg Extensions) study protocol.

INTRODUCTION: Early phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements. METHODS AND ANALYSIS: A methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions. ETHICS AND DISSEMINATION: This project was approved by ICR's Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites. REGISTRATION DETAILS: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

Adaptive Designs: Results of 2016 Survey on Perception and Use.

BACKGROUND: The DIA Adaptive Designs Scientific Working Group has a devoted subteam to performing surveys, literature reviews, and registry reviews every 4 years to assess the perception and use of adaptive designs (ADs) in the development of drugs and biologics. METHODS: A survey was distributed to pharmaceutical companies, academic institutions, and contract research organizations to collect information about the usage of ADs of different types and perception of challenges for their use. Literature and registry reviews were conducted to assess the prevalence of ADs of different types in drug and biologics development. These results were compared to previous surveys and reviews using summary statistics. RESULTS: ADs appear to be more widely considered in the last 4 years as compared to earlier 4-year periods. CONCLUSIONS: The most common types of ADs remain early stopping, treatment group adaptations, and sample size re-estimation. Both stopping early for safety and changing the endpoint of the analyses were rarely mentioned in literature prior to 2012 but are now appearing more frequently. The barriers of change management and negative experiences by some institutions with ADs remain a source of concern. Additional, consistent training would be helpful to choose the right adaptation(s) needed for specific clinical trials and for planning appropriately for operational efficiency such as for drug supply management and data management. The perceived barrier of regulatory acceptance also remains a concern, which could be alleviated by additional interaction with agencies and an update of the FDA draft guidance to industry on adaptive designs.

How to design a dose-finding study using the continual reassessment method.

INTRODUCTION: The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. METHODS: To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. RESULTS: An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. CONCLUSIONS: The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.

A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

Adaptive designs in clinical trials: why use them, and how to run and report them.

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial's course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension.

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman's disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.

Detecting Data Quality Issues in Clinical Trials: Current Practices and Recommendations.

BACKGROUND: Data quality issues in clinical trials can be caused by a variety of behaviors including fraud, misconduct, intentional or unintentional noncompliance, and significant carelessness. Regardless of how these behaviors are defined, they may compromise the validity of the study results. Reliable study results and quality data are needed to evaluate products for marketing approval and for decisions that are made on the use of medicine. This article focuses on detecting data quality issues, irrespective of origin or motive. Early detection of data quality issues are important so that corrective actions taken can be implemented during the conduct of the trial, recurrence can be prevented, and data quality can be preserved. METHODS: A survey was distributed to TransCelerate member companies to assess current strategies for detecting and mitigating risks involving fraud and misconduct in clinical trials. A review of literature across many industries from 1985 to 2014 was conducted using multiple platforms. RESULTS: Eighteen TransCelerate member companies anonymously responded to the survey. All of the respondents had one or more existing strategies for fraud and misconduct detection. The literature search identified current practices and methodologies across many industries. CONCLUSIONS: TransCelerate recommends the creation of an integrated, multifaceted approach to proactively detect data quality issues. Detection methods should include a strategy tailored to the characteristics of the study. Some sponsors are taking advantage of more advanced methods and integrated processes and systems to proactively detect and address issues, relying on advances in technology to more efficiently review data in real time. Further research is underway to assess statistical data quality detection methodology in clinical trials.

Adaptive Design: Results of 2012 Survey on Perception and Use.

Adaptive designs are increasingly used in clinical trials. The Drug Information Association's Adaptive Design Scientific Working Group (ADSWG) works to foster collaboration among regulatory agencies, academia, and pharmaceutical and biotech companies to further the science of adaptive clinical development. The ADSWG Survey Subteam has collected data on the usage of adaptive designs in clinical research from multiple sources, including a recent ADSWG survey regarding the perception and usage of adaptive designs in academia and industry for studies between 2008 and 2011, as well as barriers to usage; a literature review examining publications of adaptive design methodology and usage between 2000 and 2011; and a trial registry review of adaptive design references from 1996 to 2011. The comprehensive results of the ADSWG 2012 survey are provided in this article with comparisons to our previous 2008 survey, the literature and registry reviews, and recent surveys carried out by the US Food and Drug Administration (FDA) and the European Medicines Agency. Results of the ADSWG 2012 survey illustrate that industry and academia are showing more enthusiasm for adaptive trials, accompanied by an increase in the number of trials using designs described as less well understood in the FDA draft guidance on adaptive designs, published in 2010. The increased use of these methods in exploratory trials is consistent with the FDA draft guidance. The survey also identified several examples of successful marketing applications supported by confirmatory trials utilizing adaptive designs that were considered, at least at the time of the draft guidance, as less well understood. While some of the technological barriers to adaptive design usage identified in the 2008 survey are now less common, there are several important persistent barriers to usage. Organizations can help overcome these barriers through education, preplanning, and early engagement in discussions with the regulators.

Effects of gender, age, diabetes mellitus and renal and hepatic impairment on tadalafil pharmacokinetics.

AIMS: To evaluate the effects of gender, age, diabetes mellitus, renal and hepatic impairment on tadalafil pharmacokinetics and tolerability. METHODS: Six single-dose (5, 10 or 20 mg orally) clinical pharmacology studies were conducted in the UK, Belgium, Poland and Germany in healthy male and female subjects, elderly subjects and subjects with diabetes mellitus, renal impairment, end-stage renal failure (ESRF) or hepatic impairment. The gender study also incorporated administration of 10 mg tadalafil daily for 10 days. RESULTS: Systemic exposure in the elderly was 25% greater than in young subjects (mean AUC ratio 1.25; 90% confidence interval 0.972, 1.61). The AUC was 19% lower in subjects with diabetes mellitus than in healthy age/gender-matched controls. Pharmacokinetics in female subjects were essentially similar to those in males. Exposure in subjects with mild or moderate renal insufficiency was approximately twice that in healthy subjects. The mean AUC for the major metabolite (total methylcatechol glucuronide) in the presence of ESRF was three times the mean for healthy subjects. Haemodialysis contributed negligibly to elimination of tadalafil or the metabolite. Hepatic impairment had negligible effects on exposure. The most common adverse events in these six studies were headache, back pain and myalgia. A 10-mg dose was not well tolerated by subjects with moderate renal dysfunction in this study. CONCLUSIONS: No clinically significant effect of gender, age, diabetes mellitus or hepatic impairment on tadalafil pharmacokinetics was observed. Renal insufficiency resulted in increased systemic exposure. Tadalafil was not associated with any serious clinically significant adverse events or study discontinuations due to adverse events.

Effects of tadalafil on myocardial blood flow in patients with coronary artery disease.

OBJECTIVE: Erectile dysfunction and coronary artery disease share similar risk factors. Although phosphodiesterase-5 inhibitors used to treat erectile dysfunction do not adversely affect hemodynamic parameters in patients with coronary artery disease, their effects on myocardial blood flow are unknown. METHODS: In a randomized, double-blind, crossover study we examined the effects of tadalafil, 20 mg, compared with placebo on myocardial blood flow in patients with stable coronary artery disease (n=7, 52-73 years old). After tadalafil or placebo, myocardial blood flow was measured with positron emission tomography (nine-segment model) at rest, during maximal coronary hyperemia with adenosine, and during increased myocardial work with dobutamine. Abnormal flow was defined as myocardial blood flow <75% of maximum perfusion during adenosine plus placebo (46 normal/17 abnormal segments dentified). RESULTS: Compared with placebo, tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Similarly, in normal and abnormal segments, tadalafil versus placebo had no significant effect on resting myocardial blood flow or on adenosine-induced increases in myocardial blood flow. In normal segments, myocardial blood flow with dobutamine plus tadalafil was greater than that with dobutamine plus placebo (1.79+/-0.56 versus 1.56+/-0.37 ml/g per min, P<0.01), and in abnormal segments, there was a trend for tadalafil compared with placebo to increase myocardial blood flow during dobutamine infusion (1.46+/-0.44 versus 1.36+/-0.36 ml/g per min, P=0.7). CONCLUSIONS: Tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Compared with placebo, tadalafil significantly augmented myocardial blood flow during increased workload in normal regions, with a trend toward improving myocardial blood flow in poorly perfused regions.

Tadalafil pharmacokinetics in healthy subjects.

AIMS: To characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses. METHODS: Noncompartmental parameters were calculated for healthy subjects receiving a single 2.5-20-mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple-dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days. RESULTS: Tadalafil was absorbed rapidly with mean Cmax (378 microg l-1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h-1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once-daily administration, and accumulation (1.6-fold) was consistent with the t1/2. CONCLUSIONS: Tadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.

The effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease.

OBJECTIVE: To investigate the effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease (CAD). Background CAD and erectile dysfunction (ED) share similar risk factors. It is important to know the cardiovascular effects of tadalafil in patients with CAD during physical exertion that is comparable with sexual activity. METHODS: A randomized, placebo-controlled, double-blind, two-period, crossover study comparing the effects of tadalafil 10 mg and placebo on the time to exercise treadmill test (ETT)-induced myocardial ischaemia in subjects with stable CAD (n = 23; age range: 53-75 years, all exhibited ST-segment depression >1.5 mm at screening ETT at > 5METS). Haemodynamic responses to sublingual nitroglycerin (NTG) were assessed before and after ETT. RESULTS: Compared with placebo, tadalafil did not significantly affect the time to ETT-induced ischaemia (13 min/31 s vs. 13 min/36 s, respectively). Before exercise, NTG evoked decreases in sitting systolic blood pressure (SBP) that were significantly greater when subjects received tadalafil compared with placebo, and after exercise, more subjects experienced a decrease in SBP <85 mmHg in response to NTG after taking tadalafil vs. placebo. When subjects received tadalafil compared with placebo, SBP was lower at rest (-7 mmHg; -12,-2), during ETT (-10 mmHg; -16, -3), and after ETT (-13 mmHg; -19, -7). CONCLUSION: Tadalafil did not significantly alter the time to ETT-induced ischaemia compared with placebo in subjects with CAD. Tadalafil reduced resting and exercise SBP. Due to the potential for hypotension, the concomitant use of nitrates and tadalafil is contraindicated.

The combined use of ibutilide as an active control with intensive electrocardiographic sampling and signal averaging as a sensitive method to assess the effects of tadalafil on the human QT interval.

OBJECTIVES: This study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval. BACKGROUND: Cardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve. METHODS: Effects of tadalafil (100 mg by mouth), ibutilide (0.002 mg/kg intravenously), and placebo on the QT interval in healthy men were compared (placebo and tadalafil [n = 90], with a subset [n = 61] receiving all treatments; mean age 30 years, range 18 to 53 years). Electrocardiographic sampling was done for two days before treatment and on treatment days. The QT was corrected for RR interval with five correction methods, including an individual correction (QTcI). Plasma concentrations of tadalafil were measured to evaluate concentration-QT effect relationships. RESULTS: At the time corresponding to maximum plasma concentration of tadalafil, the mean difference in the change in QTcI between tadalafil and placebo was 2.8 ms; tadalafil was equivalent to placebo (a priori, upper limit of 90% confidence interval < 10 ms [actual = 4.4 ms]; post hoc, upper limit of 95% confidence interval < 5 ms [actual = 4.8]). The active control, ibutilide, significantly increased QTcI by 6.9 and 8.9 ms compared with tadalafil and placebo, respectively. Similar statistical results were obtained with four additional QT correction methods. No subject had a QTcI > or = 450 ms or an increase in QTcI > or = 30 ms with any treatment. CONCLUSIONS: Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.

Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo.

OBJECTIVES: Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A-mediated metabolism. METHODS: Reversible and mechanism-based inhibition of CYP3A by tadalafil was examined in human liver microsomes. The ability of tadalafil to influence CYP3A activity was also examined in primary cultures of human hepatocytes. The effect of tadalafil on the pharmacokinetics of CYP3A probe substrates was evaluated in human volunteers before and after coadministration with either a single dose or multiple doses of tadalafil (10 or 20 mg). RESULTS: Negligible competitive inhibition of CYP3A was observed in vitro. Mechanism-based inhibition of CYP3A was detected, albeit with a low potency. In human hepatocytes, exposure to 1 micromol/L or greater of tadalafil resulted in increased CYP3A protein expression; however, as with a combined effect of induction and inhibition, a corresponding increase in CYP3A activity did not occur. The clinical pharmacokinetics of midazolam and lovastatin, probe substrates of CYP3A, were unaffected by up to 14 days of tadalafil administration (90% confidence intervals for the ratio of least squares means for the pharmacokinetic parameters of tadalafil were contained within the no-effect boundaries of 0.7 to 1.43). CONCLUSIONS: In vitro results suggested that tadalafil would have little effect on the pharmacokinetics of drugs metabolized by CYP3A. Clinical studies demonstrated that the pharmacokinetics of 2 different CYP3A substrates, midazolam and lovastatin, were virtually unchanged after tadalafil coadministration. Thus therapeutic concentrations of tadalafil do not produce clinically significant changes in the clearance of drugs metabolized by CYP3A.

Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men.

PURPOSE: Tadalafil, a phosphodiesterase type 5 inhibitor, is effective therapy for erectile dysfunction (ED). Men with ED have a high incidence of comorbid conditions including cardiovascular disease, diabetes mellitus and benign prostatic hyperplasia. Although phosphodiesterase type 5 inhibitors are safe when administered with most medications, sildenafil given with doxazosin and vardenafil given with terazosin evoke orthostatic hypotension in some patients. We examined the hemodynamic interactions of tadalafil with the alpha-blockers doxazosin and tamsulosin. MATERIALS AND METHODS: In separate double-blind, placebo controlled, randomized crossover studies (18 patients in each study) we evaluated the hemodynamic effects of doxazosin 8 mg with tadalafil 20 mg, and tamsulosin 0.4 mg with tadalafil 10 and 20 mg. Blood pressure (BP) and heart rate were recorded before dosing and for 24 hours after dosing. RESULTS: Tadalafil 20 mg augmented the hypotensive effect of doxazosin by producing a mean maximal decrease in standing systolic BP (SBP) that was significantly greater than placebo (a mean difference of 9.8 mm Hg). Analysis of BP outliers showed that the number of subjects with a standing SBP of less than 85 mm Hg was greater after doxazosin plus tadalafil (28%) versus doxazosin plus placebo (6%). In subjects on tamsulosin, tadalafil 10 and 20 mg produced mean maximal decreases in standing SBP that were similar to placebo (mean difference of 1.7 and 2.3 mm Hg, respectively). No subject taking tamsulosin had a decrease in standing SBP less than 85 mm Hg. CONCLUSIONS: Tadalafil augmented the hypotensive effects of doxazosin but had little hemodynamic interaction with tamsulosin. In patients taking tadalafil for ED, tamsulosin 0.4 mg may be given for the treatment of benign prostatic hyperplasia.