Predicting QRS and PR interval prolongations in humans using nonclinical data.

BACKGROUND AND PURPOSE: Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. EXPERIMENTAL APPROACH: Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model. KEY RESULTS: Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav 1.5 block (3-7%) and Cav 1.2 binding (13-21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3-4.6% and PR 2.3-10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data. CONCLUSION AND IMPLICATIONS: Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non-arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.

Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor.

In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both q.d. and b.i.d. dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses. The model was then extended to incorporate preexisting myelosuppression where bone marrow function is inhibited by acute myeloid leukemia. Under these conditions, duration of platelet count recovery has the potential to be prolonged due to drug-induced myelosuppression.

Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters.

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.

Modeling and Simulation Approaches for Cardiovascular Function and Their Role in Safety Assessment.

Systems pharmacology modeling and pharmacokinetic-pharmacodynamic (PK/PD) analysis of drug-induced effects on cardiovascular (CV) function plays a crucial role in understanding the safety risk of new drugs. The aim of this review is to outline the current modeling and simulation (M&S) approaches to describe and translate drug-induced CV effects, with an emphasis on how this impacts drug safety assessment. Current limitations are highlighted and recommendations are made for future effort in this vital area of drug research.

Optimizing oncology therapeutics through quantitative translational and clinical pharmacology: challenges and opportunities.

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.

Factors correlated with homosexually acquired human immunodeficiency virus infection in the era of "safer sex". Was the prevention message clear and well understood? Alain Brugeat Physician Group.

A cross-sectional survey was conducted between November 1986 and January 1988 among 246 homosexual/bisexual patients by consulting physicians promoting human immunodeficiency virus (HIV) infection prevention, to determine factors correlated with HIV infection a few years after the launch of safer sex recommendations. After adjustment for numbers of sexual partners and frequency of unprotected receptive anal intercourse, seropositive subjects, compared to seronegative ones, had significantly higher frequencies of: (1) receptive anal intercourse using condoms and extraneous lubricants, (2) anorectal douching before or after intercourse, (3) past history of syphilis, and (4) nitrite inhalations. The first three factors remained significant after multivariate analysis. Eighty-three percent of the subjects practicing receptive anal intercourse with condoms plus lubricants used inappropriate lubricants. Some factors identified in our study are well established risk factors for homosexually acquired HIV infection, suggesting that safer sex recommendations still are not followed by all. Our results also elicit additional factors that independently increase the risk. Two of them, extraneous lubrication of the condom for anal receptive intercourse and anorectal douching, may result from a misunderstood notion of "safer sex," or from practices thought by mistake to protect against HIV.

[AZT in community practice]. / L'AZT en pratique de ville.

AZT is the only available antiviral treatment. While using it, several problems appear to a general practitioner. 1) The supervision of the toxic effects, which is simple but does imply an experience. 2) The interaction of several drugs, while considering, among other difficulties, the great number of similar drugs available in pharmacies. 3) The psychological investment of the patient, for whom AZT is all at a time, a threat, a coercitive weapon and a hope. A proper knowledge of these problems allows the G.P. to work in agreement with the hospital practitioner.