A call to incorporate systems theory and human factors into the existing investigation of harm in clinical research involving healthcare products.

This is a joint statement from individual pharmacology and pharmaceutical professionals acting in their own capacity, including members of the Alliance for Clinical Research Excellence and Safety (ACRES) and the International Society of Pharmacovigilance (ISoP). By building on the extensive pharmacological and regulatory investigations that already take place, we are calling for a fuller and more robust systems-based approach to the independent investigation of clinical research when serious incidents of harm occur, starting with first-in-human clinical trials. To complement existing activities and regulations, we propose an additional approach blending evidence derived from both pharmacological and organizational science, which addresses human factors and transparency, to enhance organizational learning and continuous improvement. As happens with investigations in other sectors of society, such as the chemical and aviation sector, this systems approach should be seen as an additional way to understand how problems occur and how they might be prevented in the future. We believe that repetition of potentially preventable and adverse outcomes during clinical research, by failing to identify and act upon all systematic vulnerabilities, is a situation that needs urgent change. As we will discuss further on, approaches based on applying systems theory and human factors are much more likely to improve objectivity and transparency, leading to better system design.

Limited sampling strategy of partial area under the concentration-time curves to estimate midazolam systemic clearance for cytochrome P450 3A phenotyping.

OBJECTIVE: Intravenous (IV) midazolam is the preferred cytochrome P450 (CYP) 3A probe for phenotyping, with systemic clearance (CL) estimating hepatic CYP3A activity. A limited sampling strategy was conducted to determine whether partial area under the concentration-time curves (AUCs) could reliably estimate midazolam systemic CL during conditions of CYP3A baseline activity, inhibition, and induction/activation. METHODS: Midazolam plasma concentrations during CYP3A baseline (n = 93), inhibition (n = 40), and induction/activation (n = 33) were obtained from 7 studies in healthy adults. Noncompartmental analysis determined observed CL (CL(obs)) and partial AUCs. Linear regression equations were derived from partial AUCs to estimate CL (CL(pred)) during CYP3A baseline, inhibition, and induction/activation. Preestablished criterion for linear regression analysis was r(2) ≥ 0.9. CL(pred) was compared with CL(obs), and relative bias and precision were assessed using percent mean prediction error and percent mean absolute error. RESULTS: During CYP3A baseline and inhibition, all evaluated partial AUCs failed to meet criterion of r(2) ≥ 0.9 and/or percent mean absolute error <15%. During CYP3A induction/activation, equations derived from partial AUCs from 0 to 1 hour (AUC0-1), 0 to 2 hours (AUC0-2), and 0 to 4 hours (AUC0-4) were acceptable, with good precision and minimal bias. These equations provided the same conclusions regarding equivalency testing compared with intense sampling. CONCLUSIONS: During CYP3A induction/activation, but not baseline or inhibition, midazolam partial AUC0-1, AUC0-2, and AUC0-4 reliably estimated systemic CL and consequently hepatic CYP3A activity in healthy adults.

Detection and localization of bile duct leaks after cholecystectomy using Gd-EOB-DTPA-enhanced MR cholangiography: retrospective study of 16 patients.

OBJECTIVE: To determine if gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) cholangiography can detect and localize bile duct leaks in postcholecystectomy patients. MATERIAL AND METHODS: Four blinded independent radiologists performed a retrospective review of 16 consecutive patients who underwent MR cholangiography with intravenous Gd-EOB-DTPA for the evaluation of possible biliary leak. Image quality, ductal opacification, and presence and location of any bile leak were evaluated. An independent observer determined the criterion standard using a consensus of all chart, clinical, and imaging findings. RESULTS: All 6 bile leaks confirmed at endoscopic retrograde cholangiopancreatography were diagnosed by all reviewers (sensitivity, 100%). Of the 10 patients with no leak, only one reader incorrectly diagnosed a bile leak in a single case (specificity, 98%). The accuracy for detection of the site of leak with Gd-EOB-DTPA-enhanced MR cholangiography was 80%. CONCLUSION: Gadolinium-EOB-DTPA-enhanced MR can detect bile leaks with a high sensitivity and specificity.

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults.

We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2-compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single- or 2-time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration-time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single- and 2-time point limited sampling models estimated area under the plasma concentration-time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r2 , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.

Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir.

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C(12 h)) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC(0-infinity)) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C(max)) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C(12 h) GMR (90% CI) was 0.79 (0.49, 1.28); AUC(0-infinity) was 0.64 (0.52, 0.80); and C(max) was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.

Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach.

Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2 ) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.

The pharmacokinetics of taurolidine metabolites in healthy volunteers.

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. t(max) generally occurred at the end of infusion for taurinamide, whereas that of taurultam was reached before completion of infusion. The taurolidine metabolite taurultam demonstrated a shorter half-life and lower systemic exposure than taurinamide. Shortening of infusion duration increased the C(max) and AUC of taurultam. Changes in infusion rate did not substantially change the pharmacokinetic parameters of taurinamide.

Human pharmacokinetics and interconversion of enantiomers of MK-0767, a dual PPARalpha/gamma agonist.

MK-0767, a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, has been studied as a potential treatment of type 2 diabetes and dyslipidemia. The pharmacokinetics and interconversion of (+)-(R)-MK-0767 and (-)-(S)-MK-0767 were evaluated following oral administration of each single enantiomer and the racemate to healthy subjects. The results demonstrate that, consistent with in vitro experiments, chiral inversion occurs rapidly in vivo, and interconversion equilibrium favors (+)-(R). After all treatments, a stable ratio (R/S) of 2 to 2.5 was achieved within 8 hours in most individuals, congruent with model-based estimates of interconversion half-life. In addition, the pharmacokinetics of each enantiomer were generally similar regardless of treatment. Modeling and simulation of enantiomer disposition suggest that the observed predominance of (+)-(R)-MK-0767 in plasma may result from differential volumes of distribution between (-)-(S) and (+)-(R), preferential conversion from (-)-(S) to (+)-(R), or a combination of these, but not faster clearance of (-)-(S) compared to (+)-(R).

Effect of aprepitant on the pharmacokinetics of intravenous midazolam.

Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg +/- oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound < or =2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC(0-infinity) 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Hot Button Protocol and Operational Issues Between Sponsors and Sites in Clinical Pharmacology Studies: A Moderated Forum Session.

This paper summarizes a discussion that took place at the 52nd Annual DIA Meeting in Philadelphia, PA, on June 30, 2016, titled "Hot-Button Protocol and Operational Issues between Sponsors and Sites in Clinical Pharmacology Studies." The symposium was a moderated panel of phase 1 clinical research experts representing the sponsor, and investigational sites. Conference attendees of similar experience joined in the discussion after commentary by each panelist. The learning objectives of the symposium were (1) to recognize issues that can provoke sponsor/site conflict or diminish conduct efficiency when they arise in the course of preparing to conduct or execution of phase 1 clinical studies, (2) to discuss how to handle such issues with counterparts when they arise and describe ways to negotiate and formulate a successful resolution. Sponsors and sites both have challenges in executing clinical trials on time and within budget. Both need to set and maintain realistic expectations and communicate with honesty, transparency, and timeliness. Achieving this goal will advance the more important take-away message, that developing new drugs requires sound execution of clinical trials.

Structured Risk Assessment for First-in-Human Studies.

We describe a structured risk assessment and risk mitigation process that is currently used to evaluate proposed first-in human (FiH) studies. This process balances the inherent risks of an FiH study with maximal protection of subjects. Risk assessment should consider all available data, carefully identifying aspects that may lead to risk for healthy subjects. A structured risk assessment avoids omissions and promotes consistency. Such a risk assessment should be performed for Investigational Products as well as for challenge agents and study procedures. Careful risk assessment recognizes gaps of knowledge and emphasizes that FiH studies are tolerability, not toxicity, studies.

Comprehensive review of visual defects reported with topiramate.

OBJECTIVE: The objective of this study was to analyze clinical patterns of visual field defects (VFDs) reported with topiramate treatment and assess possible mechanism of action (MOA) for antiepileptic drug (AED) associated VFDs. METHODS: A comprehensive topiramate database review included preclinical data, sponsor's clinical trials database, postmarketing spontaneous reports, and medical literature. All treatment-emergent adverse events (TEAEs) suggestive of retinal dysfunction/damage were summarized. Relative risk (RR) was computed from topiramate double-blind, placebo-controlled trials (DBPCTs) data. RESULTS: Preclinical studies and medical literature review suggested that despite sharing gamma-aminobutyric acid (GABA)-ergic MOA with other AEDs, topiramate treatment was not associated with VFDs. TEAEs suggestive of retinal dysfunction/damage were observed in 0.3%-0.7% of adults and pediatric patients with topiramate (N=4,679) versus ≤0.1% with placebo (N=1,834) in DBPCTs for approved indications (epilepsy and migraine prophylaxis); open-label trials (OLTs) and DBPCTs for investigational indications had similar incidence. Overall, 88% TEAEs were mild or moderate in severity. Serious TEAEs were very rare (DBPCTs: 0%; OLTs: ≤0.1%), and most were not treatment limiting, and resolved. The most common visual TEAEs (approved indications) were VFD, scotoma, and optic atrophy. The incidence of TEAEs in DBPCTs (approved and investigational indications) was higher in topiramate-treated (N=9,169) versus placebo-treated patients (N=5,023; 0.36% vs 0.24%), but the RR versus placebo-treated patients was not significant (RR: 1.51 [95% confidence interval: 0.78, 2.91]). CONCLUSION: VFDs do not appear to be a class effect for AEDs with GABA-ergic MOA. The RR for VFDs is not significantly different between topiramate and placebo treatment.

Safety in FIH Trials: A Summary of the Symposium "Fatal Drug Trial in Phase 1: Understanding Risk, Subject Safety, Timelines, and Cost".

A cross-section of clinical research professionals convened at the June 2016 Drug Information Association annual meeting in Philadelphia to discuss and critically analyze the first-in-human (FIH) clinical trial conducted by a French CRO with BIA 10-2474 (BIA) under development for pain relief by Bial-Portela & Ca., S.A., that resulted in 6 healthy volunteers hospitalized with serious adverse events, which resulted in 1 death. This paper summarizes the background, presentations, and discussion points of Symposium no. 107 in an effort to share the learnings of our symposium with others who conduct studies. Novel investigational products studied in phase 1 clinical trials propose a heightened risk of adverse events that may not be foreseeable when relying on animal studies to project outcomes in humans. Novelty of molecular structure, drug class, mechanism of action, proper dose selection, pharmacokinetics, and therapeutic window are all contributing factors that heighten risks when transitioning from animal to human trials. The potential for catastrophic events confronts every sponsor/investigator in clinical trials. Minimizing risks to subjects is an essential ethical and scientific mandate for all those involved in the clinical trials. A complex matrix of planning, conducting, and communicating preclinical and clinical observations need to be considered carefully by the Sponsor, Investigator and others during the planning, execution, and interpretation of FIH studies, in order to promote participant safety and study data integrity. Suggestions may be applied to FIH studies, which may provide a new or improved way to address complex system and prevent or mitigate situations such as what occurred with the Bial FIH trial, where seemingly a number of issues coincided in a "perfect storm" and the system failed to sound a warning or detect an issue before a life was tragically lost.

Effects of ezetimibe on cyclosporine pharmacokinetics in healthy subjects.

This single-center, open-label, 2-period crossover study investigated the effects of multiple-dose ezetimibe (EZE) on a single dose of cyclosporine (CyA). Healthy subjects received 2 treatments in random order with a 14-day washout: (1) CyA 100 mg alone and (2) EZE 20 mg for 7 days with CyA 100 mg coadministered on day 7; EZE 20 mg alone was administered on day 8. AUC(0-last) and Cmax geometric mean ratios (90% confidence interval) for ([CyA + EZE]/CyA alone) were 1.15 (1.07, 1.25) and 1.10 (0.97, 1.26), respectively. Tmax (approximately 1.3 hours) was similar with and without EZE (P >.200). Mean CyA exposure slightly increased (approximately 15%) with multiple-dose EZE 20 mg; however, this value was contained within (0.80, 1.25). The implications for chronic EZE dosing within the usual clinical paradigm of chronic CyA dosing have not been established; caution is recommended when using these agents concomitantly. CyA concentrations should be monitored in patients receiving EZE and CyA.

Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers.

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Is uveitis associated with topiramate use? A cumulative review.

Occasional reports of uveitis following topiramate use necessitated an investigation of relevant cases from safety databases and published biomedical literature. Data mining of the Food and Drug Administration Adverse Event Reporting System and cumulative review of cases from the global safety database (sponsor database) and published literature were conducted to assess association between topiramate use and uveitis. The Food and Drug Administration Adverse Event Reporting System search identified disproportional reporting of uveitis (n=23) and related terms (choroidal detachment, n=25; iridocyclitis, n=17). The postmarketing reporting frequency of uveitis and related events from the global safety database and based on an estimated topiramate exposure of 11,185,740 person-years from launch to April 2015 was 0.38 per 100,000 person-years and assigned as very rare. A total of 14 potential uveitis cases were identified from the cumulative review. Seven of these 14 cases were complicated by inadequate documentation, appearance of uveitic signs following drug withdrawal, or concurrent use of other sulfonamides. In acute angle-closure glaucoma and uveal effusions cases, insufficient evidence for underlying inflammation suggested that uveitis was not a component. Only seven of 14 cases were well documented, potentially topiramate-associated uveitis cases. Uveitis may occur in the setting of topiramate use only in very rare instances. Current evidence did not reveal a dose- or duration-dependent relationship between uveitis and topiramate use.

A greenhouse gas emissions inventory for Pennsylvania.

The Pennsylvania greenhouse gas (GHG) emissions inventory presented in this paper provides detailed estimates of emissions and their sources for the six major categories of GHGs. The inventory was compiled using the current U.S. Environment Protection Agency methodology, which applies emissions factors to socioeconomic data, such as fossil energy use, vehicle miles traveled, and industrial production. The paper also contains an assessment of the methodology and suggestions for improving accounting with respect to process, sectoral, and geographic considerations. The study found that Pennsylvania emitted 77.4 million metric tons carbon equivalent of GHGs in 1990 and that this total increased by 3% to 79.8 million metric tons carbon equivalent by 1999. Despite this increase, however, the state's percentage contribution to the United States total declined during the decade. Pennsylvania's carbon dioxide (CO2) emissions from fossil fuels represented 92.4% of 1990 totals and declined to 90.5% in 1999. Electricity generation was the largest single source of CO2 emissions, being responsible for 38% of fossil fuel CO2 emissions in 1990 and 40% of the total in 1999. Transportation emissions accounted for the largest increases in emissions between 1990 and 1999, whereas industrial emissions accounted for the largest decrease. The overall trend indicates that Pennsylvania has been able to weaken the relationship between GHG emissions and economic growth.

Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin.

This double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI-M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI-M excretion following single and multiple doses (P = .004 vs placebo). PGI-M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx-M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx-M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx-M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX-1 and COX-2 following a single dose, but acetaminophen was a less potent COX-1 inhibitor than indomethacin.

The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers.

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0-t), and AUC(0-infinity). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules.

Effect of mibefradil on CYP3A4 in vivo.

Mibefradil, a calcium channel blocker, was removed from the market because of adverse drug interactions with coadministered CYP3A4 substrates. This study examined the effect of mibefradil on the activity of hepatic and intestinal CYP3A4 in vivo, employing the erythromycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-period, single-blind, placebo-controlled crossover study in which 8 male volunteers were randomized to the order of receiving placebo and a single 100-mg oral dose of mibefradil. Oral midazolam was coadministered with intravenous [14C N-methyl] erythromycin 1 hour after mibefradil/placebo administration. The EBT was performed 20 minutes following erythromycin administration. Blood and urine were collected during the 36 hours following probe drug administration for analysis of midazolam pharmacokinetics. Coadministration of mibefradil increased the Cmax of midazolam 3-fold, the AUC 8- to 9-fold, and the t1/2 4-fold. Mibefradil coadministration decreased the amount of exhaled 14CO2 in 6 of 8 subjects, with a mean decrease of 25%. It was concluded that a single oral dose of mibefradil significantly inhibits CYP3A4 in intestine and liver. These data support that adverse drug interactions involving mibefradil reflect inhibition of CYP3A4 in intestine and liver. Also, they suggest that the EBT, while a valid probe of in vivo hepatic CYP3A4 activity, is a single time point measurement and may be less sensitive than oral midazolam pharmacokinetics in detecting CYP3A4 inhibition.