Systematic review and comparison of national and international guidelines on diverticular disease.

PURPOSE: Diverticular disease is common and of increasing medical and economical importance. Various practice guidelines on diagnostic and treatment on this disease exist. We compared current guidelines on the disease in order to identify concordant and discordant recommendations. METHOD: Eleven national and international guidelines on diverticular disease published over the last 10 years have been identified by a systematic literature review on PubMed and compared in detail for 20 main and 51 subtopics. RESULTS: The available evidence for the most aspects was rated as moderate or low. There was concordance for the following items: Diagnosis of diverticulitis should be confirmed by imaging methods (10 of 10 guidelines). Mild forms may be treated out-patient (10/10). Abscesses are treated non-surgically (9/9). Elective surgery should be indicated by individual patient-related factors, only, and be performed laparoscopically (10/10, 9/9 respectively). Main differences were found in the questions of appropriate classification, imaging diagnostic (computed-tomography versus ultra-sound), need for antibiotics in out-patient treatment and mode of surgery for diverticular perforation. Despite growing evidence that antibiotics are not needed for treating mild diverticulitis, only 3/10 guidelines have corresponding recommendations. Hartmann's procedure has been abandoned several years ago and is now recommended for feculent peritonitis by the three most recent guidelines. In contrast, laparoscopic lavage without resection is not recommended anymore. CONCLUSION: There are dissents in the recommendations for central aspects regarding the diagnostic and treatment of diverticular disease in recently published guidelines.

ITC commentary on the prediction of digoxin clinical drug-drug interactions from in vitro transporter assays.

The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.

Identification of the effect of multiple polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid using a population-modeling approach.

The aim of this work was to develop a joint population pharmacokinetic model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that incorporates the effects of multiple genetic polymorphisms and clinical/demographic characteristics. SV/SVA plasma concentrations, demographic/clinical data, and genotypes for 18 genetic variants were collected from 74 individuals (three clinical trials) and analyzed using a nonlinear mixed-effects modeling approach. The structural model that best described the data included a two- and a one-compartment disposition model for SV and SVA, respectively. Age, weight, Japanese ethnicity, and seven genetic polymorphisms-rs4149056 (SLCO1B1), rs776746 (CYP3A5), rs12422149 (SLCO2B1), rs2231142 (ABCG2), rs4148162 (ABCG2), rs4253728 (PPARA), and rs35599367 (CYP3A4)-were identified as significantly affecting model parameters. The developed model was used to assess combinations of these covariates, highlighting specific risk factors associated with altered SV/SVA pharmacokinetics, and consequently myopathy cases that cannot be solely attributed to the rs4149056 CC genotype.

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.

ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans.

This white paper provides a critical analysis of methods for estimating transporter kinetics and recommendations on proper parameter calculation in various experimental systems. Rational interpretation of transporter-knockout animal findings and application of static and dynamic physiologically based modeling approaches for prediction of human transporter-mediated pharmacokinetics and drug-drug interactions (DDIs) are presented. The objective is to provide appropriate guidance for the use of in vitro, in vivo, and modeling tools in translational transporter science.

Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver.

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.

Prediction of metabolic clearance using fresh human hepatocytes: comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines.

1. Predictions of in vivo intrinsic clearance from cryopreserved human hepatocytes may be systematically low. In the current study, the metabolite kinetics of a series of CYP3A4 substrates (benzodiazepines) in fresh human hepatocytes from five donors, via a major UK supplier, were investigated and compared with those previously reported (by the authors' laboratory) for cryopreserved human hepatocytes and hepatic microsomes. 2. A high incidence of autoactivation (up to tenfold) and heteroactivation (by testosterone, up to 14-fold) among the major pathways was observed. CYP capacity (V(max)) was marginally lower and 'affinity' constants (K(M), S(50)) were marginally greater compared with cryopreserved hepatocytes. 3. Average intrinsic clearance (based on maximal clearance, CL(max)) was sevenfold lower than in cryopreserved hepatocytes (reflecting sensitivity of intrinsic clearance estimation in vitro to mechanistic parameter values, particularly those involving atypical kinetics), but scaled intrinsic clearances for fresh (and cryopreserved) hepatocytes were within the range previously determined in hepatic microsomes. 4. There was no evidence from this series of studies that fresh hepatocytes provide quantitatively improved estimates of intrinsic clearance over cryopreserved hepatocytes.

Microsomal prediction of in vivo clearance and associated interindividual variability of six benzodiazepines in humans.

The intrinsic clearances (CLint) of midazolam, triazolam, diazepam, nordiazepam, flunitrazepam and alprazolam were determined from two liver banks (n=21) by formation kinetics of ten metabolites. A literature-collated database of in vivo CLint values (811 subjects) was used to assess predictions and variability. The in vivo clearance of six benzodiazepines was generally underpredicted by in vitro data and the degree of bias was in agreement with a database of structurally diverse compounds (n=37). The variability observed for in vitro clearances (11--19--fold for midazolam, diazepam and nordiazepam in liver bank 1; 101--269--fold for triazolam, flunitrazepam and alprazolam in liver bank 2) exceeded the in vivo variability for the same compounds (4--59 and 10--29, respectively). This mismatch may contribute to the bias in microsomal predictions and it highlights the need for careful selection of representative livers for human liver banks.

Comparative pharmacokinetics and bioavailability of two cotrimoxazole preparations.

The objective of this study was to assess both pharmacokinetic properties and bioavailability of a newly developed cotrimoxazole preparation (Bioprim tablets, 80 mg of trimethoprim/400 mg sulfamethoxazole), in comparison with a reference preparation commercially available (Bactrim tablets, 80 mg of trimethoprim/400 mg of sulfamethoxazole). The pharmacokinetics and bioavailability of cotrimoxazole from these preparations were compared in an open randomized crossover study in 12 healthy males. Plasma concentrations of trimethoprim and sulfamethoxazole were measured by HPLC after protein precipitation. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The obtained pharmacokinetic values (Cmax, tmax, beta, t1/2 beta, CL, Vd, AUC36, AUC infinity) of both trimethoprim and sulfamethoxazole determined in our study agreed with values reported in the literature. Westlake's and Nonparametric probability tests with the 90% confidence intervals, for both trimethoprim and sulfamethoxazole gave the differences within 80 and 120%, for all necessary measures (Cmax, tmax and AUC infinity). Statistical analysis of the data has shown that the preparations have similar pharmacokinetic profiles and therefore can be considered equally bioavailable.