Long-acting cabotegravir pharmacokinetics with and without oral lead-in for HIV PrEP.

Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with (n = 278) or without (n = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI (n = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084. Cabotegravir pharmacokinetic profiles were simulated in three populations (assigned-male-at-birth, 50%-assigned-female-at-birth, and assigned-female-at-birth) under three scenarios: first injection given (A) 1 or (B) 3 days after final OLI dose (OLI-injection gap) or (C) without OLI. The PK objective was 80% of participants achieving 4× in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC90) and 50% achieving 8× PA-IC90. Observed trough concentrations (Cτ) were similar with and without OLI (P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection Cτ remained above PK objective. Approximately 1-2 weeks after the first injection, simulated PK profiles became nearly identical among all scenarios. Without OLI, it was predicted that 80% of participants achieve 4× PA-IC90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC90 in 1.4, 2.1, and 3.8 days, respectively. Observed long-acting cabotegravir exposure was similar with or without OLI, supporting optional OLI use. Cabotegravir exposure was predicted to remain above PK objective for OLI-injection gaps of ≤3 days and rapidly achieve PK objective after first injection without OLI. Findings are consistent between assigned-male-at-birth and assigned-female-at-birth populations.This study is registered with ClinicalTrials.gov as NCT02720094.

Population pharmacokinetics and exposure-response of anti-programmed cell death protein-1 monoclonal antibody dostarlimab in advanced solid tumours.

AIM: Develop a population pharmacokinetic (PopPK) model to characterise the pharmacokinetics (PK) of anti-programmed cell death protein-1 (PD-1) antibody dostarlimab, identify covariates of clinical relevance, and investigate efficacy/safety exposure-response (ER) relationships. METHODS: A PopPK model was developed using Phase 1 GARNET (NCT02715284) trial data for dostarlimab (1, 3 or 10 mg kg-1 every 2 wk; 500 mg every 3 wk or 1000 mg every 6 wk; 500 mg every 3 wk × 4 then 1000 mg every 6 wk [recommended regimen]) serum concentrations over time. Concentration-time data were analysed using nonlinear mixed effects modelling with standard stepwise covariate modelling. ER was explored for treatment-related adverse events and overall response rate (ORR) using logistic regression. RESULTS: PopPK model/adverse event ER analyses included 546 patients (ORR ER analysis n = 362). Dostarlimab PK was well described by a 2-compartment model with time-dependent linear elimination. Time-dependent clearance decreased over time to a maximum of 14.9%. At steady state, estimated dostarlimab geometric mean coefficient of variation % clearance was 0.179 (30.2%) L d-1 ; volume of distribution was 5.3 (14.2%) L; terminal elimination half-life was 23.5 (22.4%) days. Statistically significant covariates were age, body weight, sex, time-varying albumin and alanine aminotransferase for clearance; body weight, albumin and sex for volume of distribution of the central compartment. Hepatic or renal impairment did not affect PK. There were no clinically significant ER relationships. CONCLUSION: Dostarlimab PK parameters are similar to other anti-programmed cell death protein-1 antibodies. The clinical impact of covariates on exposure was limited-to-moderate, supporting recommended dostarlimab monotherapy therapeutic dosing.

Chemopreventive and anti-angiogenic effects of dietary phenethyl isothiocyanate in an N-methyl nitrosourea-induced breast cancer animal model.

The effect of phenethyl isothiocyanate (PEITC), a component of cruciferous vegetables, on the initiation and progression of cancer was investigated in a chemically induced estrogen-dependent breast cancer model. Breast cancer was induced in female Sprague Dawley rats (8 weeks old) by the administration of N-methyl nitrosourea (NMU). Animals were administered 50 or 150 µmol/kg oral PEITC and monitored for tumor appearance for 18 weeks. The PEITC treatment prolonged the tumor-free survival time and decreased the tumor incidence and multiplicity. The time to the first palpable tumor was prolonged from 69 days in the control, to 84 and 88 days in the 50 and 150 µmol/kg PEITC-treated groups. The tumor incidence in the control, 50 µmol/kg, and 150 µmol/kg PEITC-treated groups was 56.6%, 25.0% and 17.2%, while the tumor multiplicity was 1.03, 0.25 and 0.21, respectively. Differences were statistically significant (p < 0.05) from the control, but there were no significant differences between the two dose levels. The intratumoral capillary density decreased from 4.21 ± 0.30 vessels per field in the controls to 2.46 ± 0.25 in the 50 µmol/kg and 2.36 ± 0.23 in the 150 µmol/kg PEITC-treated animals. These studies indicate that supplementation with PEITC prolongs the tumor-free survival, reduces tumor incidence and burden, and is chemoprotective in NMU-induced estrogen-dependent breast cancer in rats. For the first time, it is reported that PEITC has anti-angiogenic effects in a chemically induced breast cancer animal model, representing a potentially significant mechanism contributing to its chemopreventive activity.

Comparative analysis of PD-1 target engagement of dostarlimab and pembrolizumab in advanced solid tumors using ex vivo IL-2 stimulation data.

Dostarlimab (JEMPERLI) is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody (mAb) which is approved by the US Food and Drug Administration for patients with recurrent/advanced mismatch repair-deficient solid tumors, including endometrial cancer, following progression on prior treatment, with approval based on data from the phase I GARNET trial. To support dostarlimab dose regimen recommendations, we estimated and compared the potency of dostarlimab relative to anti-PD-1 mAb pembrolizumab using both data published from the KEYNOTE-001 trial of pembrolizumab and data from the GARNET trial. PD-1 target engagement was assessed ex vivo in blood samples via a super antigen staphylococcal enterotoxin B stimulation assay and interleukin-2 (IL-2) stimulation ratios calculated for dostarlimab. A non-linear mixed-effect sigmoid maximum effect inhibitory model was fitted to dostarlimab IL-2 stimulation ratios using extracted pembrolizumab data as informative priors. The estimated half-maximal effective concentration was 1.95 µg ml-1 (95% credibility interval: 0.21-5.87) for dostarlimab and 1.59 µg ml-1 (95% confidence interval: 0.42-6.12) for pembrolizumab. These findings suggest dostarlimab and pembrolizumab to be equipotent for peripheral PD-1 suppression based on analysis of ex vivo IL-2 stimulation ratios. Accounting for a three-fold dilution between serum and tumor, a target dostarlimab trough concentration of ~54 µg ml-1 would be needed for 90% suppression in the tumor. These data support the use of dostarlimab as a potent PD-1 suppressor and the recommended dostarlimab monotherapy dose regimen of 500 mg Q3W ×4 cycles followed by 1000 mg Q6W thereafter in recurrent/advanced solid tumors.

Reevaluation of a quantitative structure pharmacokinetic model for biliary excretion in rats.

Quantitative structure pharmacokinetic relationship (QSPKR) modeling can be used to predict the biliary clearance and percentage of dose eliminated in bile (PD(b)) in humans before clinical studies. Recently, a QSPKR model based on in-house compounds was derived using simple physicochemical descriptors to predict the PD(b) in rats (Drug Metab Dispos 38:422-430, 2010). Our objective was to evaluate the QSPKR model derived for the prediction of PD(b) for our larger dataset of 164 compounds in the rat and for the 97 compounds in our human dataset (AAPS J 11:511-525, 2009). Re-analysis of the published QSPKR model revealed the model to be statistically insignificant (Drug Metab Dispos 38:422-430, 2010). Thus, a new statistically significant QSPKR model, consisting of one less descriptor than the published model, was derived from the published data. The newly derived model performed as well as the published model in predicting the PD(b) for the training and test sets (Drug Metab Dispos 38:422-430, 2010). In contrast, the new model performed poorly in predicting the PD(b) for our larger rat (r(2) = 0.253) and human dataset (r(2) = 0.013). The poor predictions for our datasets may be due, in part, to the quality and diversity of the data used to derive and test the model. Our reevaluation suggests that hepatobiliary excretion is a process that cannot truly be captured by simple physicochemical descriptors when examining chemically dissimilar compounds. A simple approach involving a limited number of physicochemical predictors may be useful when examining a structurally similar series of compounds.

Interspecies scaling: prediction of human biliary clearance and comparison with QSPKR.

The aim of this study was to evaluate the prediction performance of various allometric scaling methods in predicting human biliary clearance (CL(b)) from data in rats or multiple animal species and to compare the prediction performance with that of quantitative structure pharmacokinetic relationship (QSPKR) models. CL(b) data of parent drugs in rats and humans were collected from the literature for 18 compounds. A simple allometric approach was applied to CL(b) or unbound CL(b) using 0.75 or 0.66 as the allometric exponent. For scaling from rat studies alone, the prediction using 0.66 as the exponent was better than that using 0.75, and a better prediction was obtained for unbound CL(b) than CL(b). For a subset of compounds, six multiple-species scaling methods were compared, with the best prediction achieved with the simple unbound CL(b) approach. However, in the absence of protein binding data, the correction with maximum life-span potential (MLP) or 'Rule of exponent' (ROE) method offered the best prediction. Overall, multiple species had better predictability than scaling with the rat alone. Comparison of predicted human CL(b) values using multiple animal species and QSPKR offered similar prediction performance. In conclusion, the results of the present study, although based on limited data, suggested that the prediction for human CL(b) by allometry was greatly improved by the incorporation of protein binding. Human CL(b) prediction using rat data alone was not satisfactory. Additionally, QSPKR provides an alternative approach to allometry for the prediction of human biliary clearance.

Model-Based Selection and Recommendation for Subcutaneous Abatacept Dose in Patients With Polyarticular Juvenile Idiopathic Arthritis.

The selective T-cell costimulation modulator abatacept is approved for treatment of adult rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA; 6-17 years [intravenous] and 2-17 years [subcutaneous]). An extrapolation approach was taken to determine subcutaneous weight-tiered doses of abatacept to evaluate in patients with pJIA. Population pharmacokinetic (PPK) and exposure-response (E-R) analyses were conducted to determine whether the weight-tiered subcutaneous regimen provides near-maximal efficacy and is therapeutically comparable to the intravenous regimen in patients with pJIA aged 2-17 years. Combined study data from intravenous or subcutaneous abatacept were used to assess clinically relevant exposure outcomes. The PPK model was developed with data from 13 phase 2/3 studies in RA and pJIA; the E-R model for the American College of Rheumatology pediatric scores (JIA-ACR 30/50/70/100 responses) in month 4 was developed with data from 2 phase 3 pJIA studies. Predefined covariates were investigated in both analyses. PPK model-predicted exposures were steady-state peak, trough (Cminss ), and time-averaged concentrations. Abatacept PK was characterized by a linear 2-compartment model (zero-order intravenous infusion, first-order subcutaneous absorption, first-order elimination); body weight was the only clinically relevant covariate. Cminss was the best exposure predictor for the JIA-ACR response: log odds for response increased in proportion to log-transformed Cminss ; JIA-ACR30 approached a plateau when Cminss ≥ 10 µg/mL. The PPK and E-R analyses demonstrated that the weight-tiered subcutaneous and intravenous abatacept dosing regimens provide near-maximal efficacy and are clinically comparable across children with pJIA who are > 2 years old.

Absence of Association Between Abatacept Exposure and Initial Infection in Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: To assess the relationship between infection risk and abatacept (ABA) exposure levels in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) following treatment with subcutaneous (SC) and intravenous (IV) ABA. METHODS: Data from 2 published studies (ClinicalTrials.gov: NCT01844518, NCT00095173) of ABA treatment in pediatric patients were analyzed. One study treated patients aged 2-17 years with SC ABA and the other treated patients aged 6-17 years with IV ABA. Association between serum ABA exposure measures and infection was evaluated using Kaplan-Meier plots of probability of first infection vs time on treatment by ABA exposure quartiles and log-rank tests. Number of infections by ABA exposure quartiles was investigated. RESULTS: Overall, 343 patients were included in this analysis: 219 patients received SC ABA and 124 patients received IV ABA. Overall, 237/343 (69.1%) patients had ≥ 1 infection over 24 months. No significant difference in time to first infection across 4 quartiles of ABA exposure levels was observed in the pooled (P = 0.45), SC (2-5 yrs: P = 0.93; 6-17 yrs: P = 0.48), or IV (P = 0.50) analyses. Concomitant use of methotrexate and glucocorticoids (at baseline and throughout) with ABA did not increase infection risk across the ABA exposure quartiles. There was no evidence of association between number of infections and ABA exposure quartiles. No opportunistic infections related to ABA were reported. CONCLUSION: In patients aged 2-17 years with pJIA, no evidence of association between higher levels of exposure to IV ABA or SC ABA and incidence of infection was observed.

Maintenance of antibody response to diphtheria/tetanus vaccine in patients aged 2-5 years with polyarticular-course juvenile idiopathic arthritis receiving subcutaneous abatacept.

BACKGROUND: Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA. FINDINGS: This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2-5 years, with ≥2 continuous months of weekly weight-tiered (10-< 25 kg [50 mg], 25-< 50 kg [87.5 mg]) subcutaneous abatacept treatment (with/without methotrexate and/or low-dose corticosteroids), who received diphtheria/tetanus vaccine prior to enrolment, were eligible. Protective antibody levels to diphtheria/tetanus (> 0.1 IU/mL), and safety, were assessed. Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6-12 and 2-< 6 months of abatacept exposure, respectively. All patients had protective antibody levels to tetanus and 26 (89.7%) patients had protective antibody levels to diphtheria. Of the 3 patients without protective antibody levels to diphtheria, each had an antibody level of 0.1 IU/mL, bordering the lower threshold of protection. Concomitant use of methotrexate and/or low-dose corticosteroids had no evident effect on antibody levels. No unexpected adverse events, including cases of diphtheria or tetanus, were reported during the 24-month period. CONCLUSIONS: Patients aged 2-5 years with pJIA who received 2-24 months of weekly subcutaneous abatacept, with or without concomitant methotrexate and/or low-dose corticosteroids, maintained effective diphtheria and tetanus vaccination protection without new safety signals. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01844518); registered May 1, 2013; https://clinicaltrials.gov/ct2/show/NCT01844518?term=NCT01844518&rank=1.

Daclatasvir: A Review of Preclinical and Clinical Pharmacokinetics.

Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30 mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90 mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.

Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection.

INTRODUCTION: Asunaprevir (ASV) is a potent, pangenotypic, twice-daily hepatitis C virus (HCV) NS3 inhibitor indicated for the treatment of chronic HCV infection. METHODS: A population pharmacokinetic (PPK) model was developed using pooled ASV concentration data from 1239 HCV-infected subjects who received ASV either as part of the DUAL regimen with daclatasvir or as part of the QUAD regimen with daclatasvir and peg-interferon/ribavirin. RESULTS: A two-compartment model with first-order elimination from the central compartment, an induction effect on clearance, and an absorption model consisted of zero-order release followed by first-order absorption adequately described ASV PK after oral administration. A typical value for ASV clearance (CL/F) was 50.8 L/h, increasing by 43% after 2 days to a CL/F of 72.5 L/h at steady-state, likely due to auto-induction of cytochrome P450 3A4 (CYP3A4). Factors indicative of hepatic function were identified as key influential covariates on ASV exposures. Subjects with cirrhosis had an 84% increase in ASV area under the concentration time curve (AUC) and subjects with baseline aspartate aminotransferase (AST) above 78 IU/L had a 58% increase in area under the concentration time curve (AUC). Asians subjects had a 46% higher steady-state AUC relative to White/Caucasian subjects. Other significant covariates were formulation, age, and gender. CONCLUSION: The current PPK model provided a parsimonious description of ASV concentration data in HCV-infected subjects. Key covariates identified in the model help explain the observed variability in ASV exposures and may guide clinical use of the drug. FUNDING: Bristol-Myers Squibb.

Daclatasvir plus asunaprevir in treatment-naïve patients with hepatitis C virus genotype 1b infection.

AIM: To assess daclatasvir plus asunaprevir (DUAL) in treatment-naïve patients from mainland China, Russia and South Korea with hepatitis C virus (HCV) genotype 1b infection. METHODS: Patients were randomly assigned (3:1) to receive 24 wk of treatment with DUAL (daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period (immediate treatment arm) or following 12 wk of matching placebo (placebo-deferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12 (SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin (70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in DUAL-treated patients compared with placebo patients during the first 12 wk (double-blind phase), and during 24 wk of DUAL in both arms combined. RESULTS: In total, 207 patients were randomly assigned to immediate (n = 155) or placebo-deferred (n = 52) treatment. Most patients were Asian (86%), female (59%) and aged < 65 years (90%). Among them, 13% had cirrhosis, 32% had IL28B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/mL. Among patients in the immediate treatment arm, SVR12 was achieved by 92% (95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate (70%). SVR12 was largely unaffected by cirrhosis (89%), age ≥ 65 years (92%), male sex (90%), baseline HCV RNA ≥ 6 million (89%) or IL28B non-CC genotypes (96%), although SVR12 was higher among patients without (96%) than among those with (53%) baseline NS5A resistance-associated polymorphisms (at L31 or Y93H). During the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving DUAL. During 24 wk of DUAL therapy (combined arms), the most common adverse events (≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities (alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued DUAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths. CONCLUSION: DUAL was well-tolerated during this phase 3 study, and SVR12 with DUAL treatment (92%) exceeded the historical SVR rate for peg-interferon plus ribavirin of 70%.

Overcoming interference with the detection of a stable isotopically labeled microtracer in the evaluation of beclabuvir absolute bioavailability using a concomitant microtracer approach.

The oral absolute bioavailability of beclabuvir in healthy subjects was determined using a microdose (100µg) of the stable isotopically labeled tracer via intravenous (IV) infusion started after oral dosing of beclabuvir (150mg). To simultaneously analyze the concentrations of the IV microtracer ([13C6]beclabuvir) and beclabuvir in plasma samples, a liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) method was initially developed. Surprisingly beclabuvir significantly interfered with the IV microtracer detection when using the selected reaction monitoring (SRM) in the assay. An interfering component from the drug substance was observed using a high resolution mass spectrometer (HRMS). The mass-to-charge (m/z) of the interfering component was -32ppm different from the nominal value for the IV microtracer and thus could not be differentiated in the SRM assay by the unit mass resolution. To overcome this interference, we evaluated two approaches by either monitoring an alternative product ion using the SRM assay or isolating the interfering component using the parallel reaction monitoring (PRM) assay on the HRMS. This case study has demonstrated two practical approaches for overcoming interferences with the detection of stable isotopically labeled IV microtracers in the evaluation of absolute bioavailability, which provides users the flexibility in using either LC-MS/MS or HRMS to mitigate unpredicted interferences in the assay to support microtracer absolute bioavailability studies.

Biliary excretion in dogs: evidence for a molecular weight threshold.

Molecular weight (MW) is known as an important factor of biliary excretion in rats, guinea pigs, rabbits and humans. The objective of this study was to evaluate the relationship between the biliary excretion and MW of drugs in dogs. Data on the percentage of dose excreted into bile as parent drug (PD(b)) in dogs were collected from the literature for 134 compounds. Receiver operating characteristic (ROC) curve analysis was utilized to determine whether a MW threshold exists for PD(b). A MW threshold of 375-400 Da was established for anions in dogs, which is similar with the cutoff value observed in rats (400 Da) but lower than the one in humans (475 Da). No MW threshold was found for cations or cations/neutral compounds. A molecular volume threshold of 300A(3) was also determined for anions in dogs, which corresponds to a MW of 394 Da. In conclusion, our analysis suggested the presence of a MW cutoff for anions in dogs, which may be related with the molecular size of a compound. This represents the first report of the influence of MW or molecular volume as a determinant of biliary excretion for a structurally diverse set of compounds in dogs.

Structure-activity relationships and quantitative structure-activity relationships for breast cancer resistance protein (ABCG2).

Breast cancer resistance protein (ABCG2), the newest ABC transporter, was discovered independently by three groups in the late 1990s. ABCG2 is widely distributed in the body with expression in the brain, intestine, and liver, among others. ABCG2 plays an important role by effluxing drugs at the blood-brain, blood-testis, and maternal-fetal barriers and in the efflux of xenobiotics at the small intestine and kidney proximal tubule brush border and liver canalicular membranes. ABCG2 transports a wide variety of substrates including HMG-CoA reductase inhibitors, antibiotics, and many anticancer agents and is one contributor to multidrug resistance in cancer cells. Quantitative structure-activity relationship (QSAR) models and structure-activity relationships (SARs) are often employed to predict ABCG2 substrates and inhibitors prior to in vitro and in vivo studies. QSAR models correlate in vivo biological activity to physicochemical properties of compounds while SARs attempt to explain chemical moieties or structural features that contribute to or are detrimental to the biological activity. Most ABCG2 datasets available for in silico modeling are comprised of congeneric series of compounds; the results from one series usually cannot be applied to another series of compounds. This review will focus on in silico models in the literature used for the prediction of ABCG2 substrates and inhibitors.

Prediction of biliary excretion in rats and humans using molecular weight and quantitative structure-pharmacokinetic relationships.

The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure-pharmacokinetic relationships (QSPKR) to predict biliary clearance (CL(b)) and percentage of administered dose excreted in bile as parent drug (PD(b)) in rats and humans. CL(b) and PD(b) data were collected from the literature for rats and humans. Receiver operating characteristic curve analysis was utilized to determine whether a MW threshold exists for PD(b). Stepwise multiple linear regression (MLR) was used to derive QSPKR models. The predictive performance of the models was evaluated by internal validation using the leave-one-out method and external test groups. A MW threshold of 400 Da was determined for PD(b) for anions in rats, while 475 Da was the cutoff for anions in humans. MW thresholds were not present for cations or cations/neutral compounds in either rats or humans. The QSPKR model for human CL(b) showed a significant correlation (R (2) = 0.819) with good prediction performance (Q (2) = 0.722). The model was further assessed using a test group, yielding a geometric mean fold-error of 2.68. QSPKR models with significant correlation and good predictability were also developed for CL(b) in rats and PD(b) data for anions or cation/neutral compounds in rats and humans. Both CL(b) and PD(b) data were further evaluated for subsets of MRP2 or P-glycoprotein substrates, and significant relationships were derived. QSPKR models were successfully developed for biliary excretion of non-congeneric compounds in rats and humans, providing a quantitative prediction of biliary clearance of compounds.