Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC 50 values > 30 mM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC 50 = 1.9 mM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.

ABSTRACT:There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolized drug desipramine resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in bupropion clearance, and bupropion and its major active metabolite, hydroxybupropion, are not strong CYP2D6 inhibitors in vitro. The aims of this study were to investigate whether bupropion's reductive metabolites, threohydrobupropion and erythrohydrobupropion, contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, erythrohydrobupropion and threohydrobupropion were more potent inhibitors of CYP2D6 activity (K i ‫؍‬ 1.7 and 5.4 M, respectively) than hydroxybupropion (K i ‫؍‬ 13 M) or bupropion (K i ‫؍‬ 21 M). Furthermore, neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors. Using the in vitro kinetic constants and estimated liver concentrations of bupropion and its metabolites, modeling was able to predict within 2-fold the increase in desipramine exposure observed when coadministered with bupropion. This work indicates that the reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo and provides a mechanistic explanation for the clinical drug-drug interaction between bupropion and desipramine.Bupropion is a norepinephrine/dopamine reuptake inhibitor currently indicated for the treatment of major depressive disorder (Wellbutrin; GlaxoSmithKline, Research Triangle Park, NC) and smoking cessation (Zyban; GlaxoSmithKline). Clinical interactions involving bupropion and coadministered CYP2D6 substrates desipramine (Shad and Preskorn 1997;Jefferson et al., 2005), dextromethorphan (Güzey et al., 2002;Kotlyar et al., 2005), and venlafaxine (Kennedy et al., 2002) are well documented. However, CYP2D6 plays an insignificant role in bupropion clearance. In humans, bupropion is extensively metabolized to three active metabolites: hydroxybupropion, which is formed primarily via CYP2B6, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group (Schroeder, 1983;Golden et al., 1988;Faucette et al., 2000;Hesse et al., 2000). Presumably, the mechanism for the clinical interaction with desipramine, which is primarily eliminated via CYP2D6 (Gram, 1974;Distlerath and Guengerich, 1984;Brøsen et al., 1986), is the result of CYP2D6 inhibition by bupropion and/or its metabolite(s). However, published data show that bupropion and hydroxybupropion are weak CYP2D6 inhibitors in vitro (IC 50 ϭ 58 and 74 M, respectively) (Hesse et al., 2000). Because unbound human plasma concentrations of the active metabolites are 2.3-to 12-fold higher than bupropion levels, it is possible that the CYP2D6 inhibition observed in the clinic is the result of more potent CYP2D6 inhibition by threohydrobupropion or erythrohydrobupropion compared with bupropion and hydroxybupropion. In addition, another hypothesis...

Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug-drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

Physiologically based pharmacokinetic modeling and simulation can be used to predict the pharmacokinetics of drugs in human populations and to explore the effects of varying physiologic parameters that result from aging, ethnicity, or disease. In addition, the effects of concomitant medications on drug exposure can be investigated; prediction of the magnitude of drug interactions can impact regulatory communications or internal decision-making regarding the requirement for a clinical drug interaction study. Modeling and simulation can also help to inform the design and timings of clinical drug interaction studies, resulting in more efficient use of limited resources and improved planning in addition to promoting mechanistic understanding of observed drug interactions. These approaches have been used in GlaxoSmithKline from drug discovery to registration and have been applied to 41 drugs from a number of therapeutic areas. This report highlights the variety of questions that can be addressed by prospective or retrospective application of modeling and simulation and the impact this can have on clinical drug development (from candidate selection through clinical development to regulatory submissions).