Utilizing PBPK Modeling to Evaluate the Potential of a Significant Drug-Drug Interaction Between Clopidogrel and Dasabuvir: A Scientific Perspective.

Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-ß-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK.

Direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection: Interferon free is now.

Chronic hepatitis C (CHC) is a global, serious, and life-threatening disease. Virologic response at 12 weeks post-treatment (SVR12) signifies a durable virologic response and is currently the primary efficacy endpoint used in registrational trials. This change led to more rapid clinical development and earlier approvals of highly effective and well-tolerated therapies, facilitating access to those in need. Hepatitis C virus (HCV) infection is a therapeutic area where mathematical modeling has proven helpful in understanding the drug mechanism and characterizing viral kinetics to inform therapy decisions. The availability of direct-acting antivirals (DAAs) provides various treatment options for HIV/HCV coinfected patients, but the complexity of predicting and managing drug-drug interactions presents a unique challenge. Real-world experience or noninterventional studies can provide insight regarding the safety and use of therapeutics that may not be readily available from traditional clinical trials. This article provides a brief overview of the development of promising drugs for the treatment of CHC.

Justification of noninferiority margin: methodology considerations in an exposure-response analysis.

The pivotal clinical trial to support the indication of liver transplantation for everolimus was based on a noninferiority trial design. The unique trial design made it impossible to estimate the noninferiority margin at the design stage. Even though the trial was conducted based on a noninferiority margin of 12% for the primary efficacy endpoint, the lack of consensus on this margin made the efficacy results difficult to interpret. A novel pharmacometric approach was applied to derive a new margin. Even though it was smaller than 12%, the new margin was large enough so that the observed efficacy results became interpretable. This novel analysis was an important contributor to the "totality of evidence" approach that led to the approval of everolimus for the new indication. This approval represents the approval of a new drug in more than 10 years for the indication of liver transplantation.

Combining forces to combat infectious diseases.

Because the threat of infectious diseases can cause widespread fear in a community, these diseases receive much public attention. Collaborations that bring together industry, academia, regulators, and the public can lead to improved and accelerated drug development. The collaborations must be grounded in strong science and expertise in clinical trials. Development of drugs to treat infections caused by resistant bacteria, drugs to treat hepatitis C virus (HCV), and drugs to prevent HIV is taking advantage of these collaborations.

Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug.

Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25-fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time-dependent inhibition had no NPE and reasonable PPE rates (15-18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25-fold change in midazolam AUC appears appropriate.

Acceleration of drug development: a collaboration of many stakeholders.

Modern drugs are used to treat and prevent diseases that previously led to morbidity and mortality. There is a high cost to this achievement--investment for each successful drug can exceed $1.8 billion. Late-phase drug candidate failure decreases efficiency of drug development because each failure represents lost or delayed opportunity to develop successful drugs. Collaboration of stakeholders and the use of new science and knowledge management can reduce late-phase failure and accelerate drug development.

Achieving the promise of personalized medicine.

Individualized therapy is the practice of tailoring therapeutic intervention to a patient's disease, demographic characteristics, genetics, environment, lifestyle, and health status. In addition to previous methods of individualization, individualization based on pharmacogenomics is an emerging practice. Although tools are available to aid the determination of the need to individualize therapy, there are barriers to implementation. Various institutions have instituted programs to demonstrate the benefit of individualization, including programs that involve preemptive genotyping.

Predicting drug interaction potential with a physiologically based pharmacokinetic model: a case study of telithromycin, a time-dependent CYP3A inhibitor.

Telithromycin is a substrate and an inhibitor of cytochrome P450 3A (CYP3A4), with dose- and time-dependent nonlinear pharmacokinetics (PK). We hypothesized that the time-dependent inhibition (TDI) of CYP3A4 was responsible for the nonlinear PK of telithromycin and then used physiologically based PK (PBPK) modeling and simulation to verify this mechanism. Telithromycin PBPK models integrating in vitro, in silico, and in vivo PK data ruled out the contribution of enzyme/transporter saturation and suggested that TDI is a plausible mechanism for PK nonlinearity. The model successfully predicted the clinical interaction with the CYP3A4 substrate midazolam, as verified by external data not used for the model-building (intravenous (i.v.) and oral (p.o.) midazolam area under the concentration-time curve (AUC) ratio with/without concurrent telithromycin administration: 3.26 and 6.72 predicted vs. 2.20 and 6.11 observed, respectively). Models assuming reversible inhibition failed to predict such strong CYP3A4 inhibition. In the absence of in vitro TDI data, a PBPK model can be used to incorporate TDI mechanisms based on nonlinear PK data to predict clinical drug-drug interactions.

Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review.

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

A regulatory viewpoint on transporter-based drug interactions.

1. Pharmacokinetic drug interactions can lead to serious adverse events and the evaluation of a new molecular entity's (NME) drug-drug interaction potential is an integral part of drug development and regulatory review before its market approval. Clinically relevant interactions mediated by transporters are of increasing interest in clinical development and research in this emerging area and it has been revealed that drug transporters can play an important role in modulating drug absorption, distribution, metabolism and elimination. 2. Acting alone or in concert with drug-metabolizing enzymes transporters can affect the pharmacokinetics and/or pharmacodynamics of a drug. The newly released drug interaction guidance by the US Food and Drug Administration (USFDA) includes new information addressing drug transporter interactions with a primary focus on P-glycoprotein (P-gp, ABCB1). 3. This paper provides a regulatory viewpoint on transporters and their potential role in drug-drug interactions. It first outlines information that might be needed during drug development and ultimately included in new drug application (NDA) submissions to address potential transporter-mediated drug interactions. Next, it explains criteria that may warrant conduct of in vivo P-gp-mediated drug interaction studies based on in vitro assessment. In addition, it includes a review case that describes the evaluation of data suggesting a P-gp-based induction interaction.

Comparison of Light-Cycler PCR, enzyme immunoassay, and tissue culture for detection of herpes simplex virus.

A rapid PCR method was developed using the Roche LightCycler technology for detection of Herpes Simplex Virus I and II. The Lightcycler method was compared with tissue culture and direct HSV antigen detection using routine clinical samples. The LightCycler PCR was shown to be more sensitive than isolation by tissue culture (sensitivity of culture versus PCR 78%) and HSV antigen detection (sensitivity of EIA versus PCR 56%). The amplified product may be typed without additional tests. The LightCycler PCR method provides a rapid method for HSV detection that correlates well with established tests.

Factors associated with physician involvement in care management.

BACKGROUND: Enthusiasm for the concept of care management (CM) has led to unprecedented growth in the number of guidelines and protocols, but provider organizations have struggled to enlist the active support and participation of physicians in CM activities. OBJECTIVES: To empirically examine the factors influencing physician participation in and attitudes toward CM activities. METHODS: Data on 1,514 physicians were used to predict physician attitudes toward CM and their perceptions of group CM behaviors. Dependent variables were modeled using two-stage Heckman selection bias models with fixed effects corrections. Independent predictors included physician- and group-level controls as well as six potential CM participation and attitude facilitators. RESULTS: Physician participation in the implementation phase of CM activities was positively related to participation and attitude. However, physician participation in the development phase may be negatively related to later participation in CM activities. Management involvement in development phase has mixed effects (positive or no effect), but their involvement in the implementation phase was somewhat negatively related to CM participation and attitude. Financial incentives for participation in CM activities and presence of a useful management information system also appeared to be positively related to attitude and participation. CONCLUSIONS: Appropriate physician and management involvement, as well as financial incentives and useful management information systems may facilitate physician participation in CM activities. Physician involvement in implementation of CM practices appears to be important, whereas their involvement in the development phase may be negatively related to later attitudes and participation. The findings call for a more in-depth understanding of the timing of physician input in CM activities.

Assessing the impact of total quality management and organizational culture on multiple outcomes of care for coronary artery bypass graft surgery patients.

OBJECTIVES: To assess the impact of total quality management (TQM) and organizational culture on a comprehensive set of endpoints of care for coronary artery bypass graft surgery (CABG) patients, including risk-adjusted adverse outcomes, clinical efficiency, patient satisfaction, functional health status, and cost of care. METHODS: Prospective cohort study of 3,045 eligible CABG patients from 16 hospitals using risk-adjusted clinical outcomes, functional health status, patient satisfaction, and cost measures. Implementation of TQM was measured by a previously validated instrument based on the Baldridge national quality award criteria. Organizational culture was measured by a previously validated 20-item instrument. Generalized estimating equations were used to control for potential selection bias, repeated measures, and intraclass correlation. RESULTS: A 2- to 4-fold difference in all major clinical CABG care endpoints was observed among the 16 hospitals, but little of this variation was associated with TQM or organizational culture. Patients receiving CABG from hospitals with high TQM scores were more satisfied with their nursing care (P = 0.005) but were more likely to have lengths of stay >10 days (P = 0.0003). A supportive group culture was associated with shorter postoperative intubation times (P = 0.01) but longer operating room times (P = 0.004). A supportive group culture was also associated with higher patient physical (P = 0.005) and mental (P = 0.01) functional health status scores 6 months after CABG. CONCLUSIONS: There was little effect of TQM and organizational culture on multiple endpoints of care for CABG patients. There is a need to examine further the relationships among individual professional skills and motivations, group and microsystem team processes, specifically tailored interventions, and organization-wide culture, decision support processes, and incentives. Assessing the impact of such multifaceted approaches is an important area for further research.

The cost of efforts to improve quality.

BACKGROUND: Virtually all hospitals in the United States report that they engage in efforts to improve quality, such as continuous quality improvement (CQI). Little is known about the costs of these efforts and whether they are associated with improved outcomes or lower patient-care costs. OBJECTIVES: The principal objective of this study was to provide benchmark data on the costs of efforts to improve quality. The authors also attempted to determine if quality improvement expenditures are correlated with outcomes and/or condition-specific hospital costs. METHODS: Detailed information on the cost of quality improvement was obtained from hospitals participating in a broad study of CQI activities. These data were correlated with patient outcomes and condition-specific costs. The subjects were medium to large hospitals throughout the United States. Senior managers provided budgetary information on direct costs of quality improvement, and details about meetings associated with quality improvement. They also provided summary medical bills for all patients undergoing total hip replacement and coronary artery bypass graft surgery. The billing information was combined with data provided by the Health Care Finance Administration to estimate condition-specific costs. Patients were directly surveyed to obtain information about satisfaction and outcomes. RESULTS: There is a wide range of expenditures on quality improvement activities. Meeting costs are a substantial percentage of total costs. Neither total costs nor meeting costs are correlated with condition-specific costs. DISCUSSION: Hospital managers can be expected to insist on evidence that quality improvement expenditures produce tangible benefits. This article provides benchmark estimates of those benefits and a methodology for further research.

The influence of renal function on the pharmacokinetics and pharmacodynamics and simulated time course of doxacurium.

UNLABELLED: Doxacurium's clearance (C1) is markedly decreased in patients with renal failure undergoing kidney transplantation. However, no studies have determined the influence of renal function (as assessed by creatinine clearance [CrCl]) on its pharmacokinetics in patients without renal failure. We studied 53 patients aged 19-59 yr. During N2O/isoflurane anesthesia, doxacurium was infused over 10 min, plasma was sampled for up to 6 h, and twitch tension was measured. A three-compartment model was fit to plasma concentration data and an effect compartment model to twitch data. Mixed-effects modeling was used to determine the influence of covariates, including CrC1, on doxacurium's pharmacokinetic/pharmacodynamic parameters. Obesity decreased both doxacurium's Cl (1.1% per percent above ideal body weight [IBW]) and its neuromuscular junction sensitivity (0.4% per percent above IBW). Cl increased 0.6% per mL/min increase in CrCl. In addition, the rate constant for equilibration between plasma concentration and effect decreased 46% per 1% increase in isoflurane, central compartment volume decreased 86% per 1% increase in isoflurane concentration, and slow distributional Cl decreased 69% per mg/ 100 mL increase in serum albumin. Simulations showed that the latter two covariates influence the time course of bolus doxacurium administration minimally. Both obesity and renal dysfunction prolong doxacurium's recovery markedly. When dosing is based on IBW, effects of CrCl on neuromuscular recovery are smaller compared with dosing based on actual weight. Therefore, obese patients should be dosed based on IBW. No further dosage adjustment is necessary for patients with renal dysfunction; however, recovery will take longer in patients with moderate-to-severe renal dysfunction. IMPLICATIONS: We examined the factors influencing doxacurium's pharmacokinetic and pharmacodynamic characteristics. Both creatinine clearance and obesity significantly influence its time course. The effect of obesity is minimized if patients are dosed based on ideal body weight.

Effect of pancreatico-biliary secretions and GI transit time on the absorption and pharmacokinetic profile of ranitidine in humans.

PURPOSE: Ranitidine plasma concentration vs. time profiles and the extent of ranitidine absorption were examined in the presence and absence of pancreatico-biliary secretions in order to elucidate factors which may contribute to secondary peaks after oral ranitidine administration. METHODS: Ranitidine solution (300 mg) was administered to 4 fasting healthy subjects via an indwelling small-bore oroenteric tube located approximately 16 cm distal to the pylorus On 3 consecutive days, subjects randomly received ranitidine alone (control), ranitidine 10 min after 0.04 micrograms/kg IV cholecystokinin (CCK) sufficient to cause gall bladder emptying into the duodenum, and ranitidine 30 min after inflation of an occlusive duodenal balloon located approximately 10 cm distal to the pylorus to prevent pancreatico-biliary secretions from reaching the dosing port or beyond. Small bowel transit time (SBTT; min) was measured by breath H2. Serial blood samples, obtained over 12 hours in each treatment, were analyzed by HPLC to determine ranitidine AUC0-12 (ng*h/mL), as well as Cmax (ng/mL) and Tmax (min) of the first and subsequent peaks, if subsequent peaks were observed. RESULTS: Ranitidine AUC0-12 and Cmax were not altered significantly by treatments; treatment effects on SBTT varied. Secondary peaks were observed in subjects #1 and #3 during the control treatment and subjects #2 and #4 during the CCk treatment. No secondary peaks were observed in any subject during the balloon treatment, and Tmax1 was delayed. CONCLUSIONS: Results support the hypothesis that pancreatico-biliary secretions (present in the intestinal lumen during control or CCK treatment) and gastrointestinal transit time may influence the occurrence of secondary peaks in ranitidine concentration vs. time profiles.

Effects of anticholinergic medication on memory in schizophrenia.

Verbal memory and reaction time of ten schizophrenic patients were compared at two different serum anticholinergic levels. Verbal recall was worse at higher drug levels, while reaction time tended to be improved by anticholinergic treatment. Implications for studies of memory in schizophrenia are considered.