Browsing by Subject "pharmacokinetics"

Now showing 1 - 8 of 8
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    Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer
    (AACR, 2016-03) Montgomery, Bruce; Eisenberger, Mario A.; Rettig, Matthew B.; Chu, Franklin; Pili, Roberto; Stephenson, Joseph J.; Vogelzang, Nicholas J.; Koletsky, Alan J.; Nordquist, Luke T.; Edenfield, William J.; Mamlouk, Khalid; Ferrante, Karen J.; Taplin, Mary-Ellen; Department of Medicine, IU School of Medicine
    Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. Experimental Design: In ARMOR1, 49 patients received increasing doses (650–2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700–3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition.
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    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy
    (Wiley, 2019-04-21) Desta, Zeruesenay; Gammal, Roseann S.; Gong, Li; Whirl-Carrillo, Michelle; Gaur, Aditya H.; Sukasem, Chonlaphat; Hockings, Jennifer; Myers, Alan; Swart, Marelize; Tyndale, Rachel F.; Masimirembwa, Collen; Iwuchukwu, Otito F.; Chirwa, Sanika; Lennox, Jeffrey; Gaedigk, Andrea; Klein, Teri E.; Haas, David W.; Medicine, School of Medicine
    The human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.
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    Comparison of Vancomycin Pharmacokinetics in Cystic Fibrosis Patients Pre and Post-lung Transplant:
    (Sage, 2020-06-15) White, Shannon; Sakon, Colleen; Fitzgerald, Linda; Kam, Charissa; McDade, Erin; Wong, Alanna; School of Education
    Background: Vancomycin is commonly used to treat acute cystic fibrosis (CF) exacerbations associated with methicillin-resistant Staphylococcus aureus (MRSA). Multiple studies have demonstrated pharmacokinetic differences of antimicrobials in the CF population. Very little data exist regarding pharmacokinetics postlung transplant, but 2 studies have noted changes in tobramycin pharmacokinetics. No such studies exist evaluating vancomycin in CF patients postlung transplant. Methods: A retrospective cohort review of CF patients who underwent lung transplantation and received vancomycin pre- and posttransplant was conducted. CF patients who underwent transplant between 2007 and 2016 at 4 medical centers throughout the United States were included. The primary endpoint was the change in elimination rate constant. The secondary endpoints were subgroup analyses of patients grouped by age, time posttransplant, and number of nephrotoxic medications. Results: A total of 25 patients were included, of which just under half were pediatric. Patients were significantly older and heavier posttransplant and had higher serum creatinine and number of nephrotoxic medications. The change in elimination rate constant from pre- to posttransplant was −0.50 hr−1 which was statistically significant (P < .001). This significant decrease was consistent among all subgroups of patients evaluated with the exception of pediatric patients. Conclusion: Vancomycin pharmacokinetics are significantly altered in CF patients in the posttransplant setting as evidenced by a decrease in elimination rate constant. This decrease may be related to a decrease in renal clearance and higher numbers of nephrotoxic medications posttransplant. Regardless, pretransplant vancomycin regimens may not predict appropriate posttransplant regimens.
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    ELEVATED PHENYLACETIC ACID LEVELS DO NOT CORRELATE WITH ADVERSE EVENTS IN PATIENTS WITH UREA CYCLE DISORDERS OR HEPATIC ENCEPHALOPATHY AND CAN BE PREDICTED BASED ON THE PLASMA PAA TO PAGN RATIO
    (Elsevier, 2013-12) Mokhtarani, M.; Diaz, G.A.; Rhead, W.; Berry, S.A.; Lichter-Konecki, U.; Feigenbaum, A.; Schulze, A.; Longo, N.; Bartley, J.; Berquist, W.; Gallagher, R.; Smith, W.; McCandless, S.E.; Harding, C.; Rockey, D.C.; Vierling, J.M.; Mantry, P.; Ghabril, M.; Brown, R.S.; Dickinson, K.; Moors, T.; Norris, C.; Coakley, D.; Milikien, D.A.; Nagamani, SC; LeMons, C.; Lee, B.; Scharschmidt, B.F.; Department of Medicine, IU School of Medicine
    Background Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100), both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. Methods The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients ≥2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. Results Only 0.2% (11) of 4683 samples exceeded 500 ug/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio > 2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels > 500 μg/ml. Conclusions The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.
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    A genetic algorithm based global search strategy for population pharmacokinetic/pharmacodynamic model selection
    (Wiley, 2015-01) Sale, Mark; Sherer, Eric A.; Department of Medicine, IU School of Medicine
    The current algorithm for selecting a population pharmacokinetic/pharmacodynamic model is based on the well-established forward addition/backward elimination method. A central strength of this approach is the opportunity for a modeller to continuously examine the data and postulate new hypotheses to explain observed biases. This algorithm has served the modelling community well, but the model selection process has essentially remained unchanged for the last 30 years. During this time, more robust approaches to model selection have been made feasible by new technology and dramatic increases in computation speed. We review these methods, with emphasis on genetic algorithm approaches and discuss the role these methods may play in population pharmacokinetic/pharmacodynamic model selection.
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    Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers
    (American Society for Microbiology, 2016-11) Desta, Zeruesenay; Metzger, Ingrid F.; Thong, Nancy; Lu, Jessica B. L.; Callaghan, John T.; Skaar, Todd C.; Flockhart, David A.; Galinsky, Raymond E.; Medicine, School of Medicine
    Cytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t1/2) and increased both the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 h to t (AUC0-t) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P < 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC0-t ranged from 0.4% to ∼224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P < 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC0-t (Pearson r = >0.8; P < 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selective in vivo probe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability. (This study is registered at ClinicalTrials.gov under identifier NCT01104376.).
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    Modeling and simulation applications with potential impact in drug development and patient care
    (2014) Li, Claire; Bies, Robert R.; Foroud, Tatiana; Li, Lang; Renbarger, Jamie L.
    Model-based drug development has become an essential element to potentially make drug development more productive by assessing the data using mathematical and statistical approaches to construct and utilize models to increase the understanding of the drug and disease. The modeling and simulation approach not only quantifies the exposure-response relationship, and the level of variability, but also identifies the potential contributors to the variability. I hypothesized that the modeling and simulation approach can: 1) leverage our understanding of pharmacokinetic-pharmacodynamic (PK-PD) relationship from pre-clinical system to human; 2) quantitatively capture the drug impact on patients; 3) evaluate clinical trial designs; and 4) identify potential contributors to drug toxicity and efficacy. The major findings for these studies included: 1) a translational PK modeling approach that predicted clozapine and norclozapine central nervous system exposures in humans relating these exposures to receptor binding kinetics at multiple receptors; 2) a population pharmacokinetic analysis of a study of sertraline in depressed elderly patients with Alzheimer’s disease that identified site specific differences in drug exposure contributing to the overall variability in sertraline exposure; 3) the utility of a longitudinal tumor dynamic model developed by the Food and Drug Administration for predicting survival in non-small cell lung cancer patients, including an exploration of the limitations of this approach; 4) a Monte Carlo clinical trial simulation approach that was used to evaluate a pre-defined oncology trial with a sparse drug concentration sampling schedule with the aim to quantify how well individual drug exposures, random variability, and the food effects of abiraterone and nilotinib were determined under these conditions; 5) a time to event analysis that facilitated the identification of candidate genes including polymorphisms associated with vincristine-induced neuropathy from several association analyses in childhood acute lymphoblastic leukemia (ALL) patients; and 6) a LASSO penalized regression model that predicted vincristine-induced neuropathy and relapse in ALL patients and provided the basis for a risk assessment of the population. Overall, results from this dissertation provide an improved understanding of treatment effect in patients with an assessment of PK/PD combined and with a risk evaluation of drug toxicity and efficacy.
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    Ondansetron Exposure Changes in a Pregnant Woman
    (Wiley, 2016-09) Lemon, Lara S.; Zhang, Hongfei; Hebert, Mary F.; Hankins, Gary D.; Haas, David M.; Caritis, Steve N.; Venkataramanan, Raman; Obstetrics and Gynecology, School of Medicine
    Pregnancy results in many physiologic changes that can alter the pharmacokinetic profiles of medications used during pregnancy. One of the primary factors leading to these pharmacokinetic changes is altered activity of drug-metabolizing enzymes. Ondansetron is a substrate of cytochrome P450 (CYP) 3A4 (primary metabolic pathway), 2D6, and 1A2, all of which are altered during pregnancy. We evaluated the pharmacokinetics of ondansetron at three different gestational time points in a 26-year-old, pregnant, Caucasian woman with normal liver and kidney function, who was maintained on ondansetron 8 mg administered orally 3 times/day throughout her pregnancy. Serial plasma samples were collected from the subject over one 8-hour dosing interval at 14, 24, and 35 weeks’ gestation (representing early-, mid-, and late-pregnancy time points, respectively). Ondansetron plasma concentrations were determined using liquid chromatography-tandem mass spectrometry. Ondansetron area under the plasma concentration–time curve decreased progressively across gestation (634 ng hr/ml in early pregnancy, 553 ng hr/ml in mid-pregnancy, and 387 ng hr/ml in late pregnancy), with a corresponding increase in apparent oral clearance (12.6 L/hr in early-pregnancy, 14.5 L/hr in midpregnancy, and 20.7 L/hr in late-pregnancy). The decreased area under the plasma concentration–time curve and exposure to ondansetron across gestation is likely due to increased activity of CYP3A4 and CYP2D6 during pregnancy. We were not able to study this patient during the postpartum period; however, as with other CYP3A4 and CYP2D6 substrates, the apparent activities of these isoenzymes are likely return to baseline. To our knowledge, this is the first report to describe ondansetron pharmacokinetics across gestation. Additional pharmacokinetic and pharmacodynamic data are needed to confirm our results and to evaluate clinical impact; however, in the meantime, clinicians should be aware of these pharmacokinetic changes in ondansetron exposure during pregnancy.