Drug–drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in... more Drug–drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically‐based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2‐hour dose separation or dabigatran etex...
We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopri... more We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopristin, and eperezolid (formerly known as U-100,592) against four strains of enterococci. All regimens tested resulted in the growth inhibition of each isolate. Against the three clinafloxacin-susceptible strains, clinafloxacin tested alone was the most active treatment, decreasing the bacterial inoculum by more than 3 log10 CFU/ml after 24 h in time-kill curve studies.
The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of po... more The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of poorly water-soluble drugs in a children-friendly, flexible solid dosage form. For diseases like HIV, pediatric patients are taking multiple drugs for effective treatments. Fixed-dose combinations could reduce pill burdens and costs as well as improving patient adherence. However, development of fixed-dose combinations of poorly water-soluble drugs for pediatric formulations is very challenging. We discovered a novel nanotechnology that produced in situ self-assembly nanoparticles (ISNPs) when the ISNP granules were introduced to water. In this study, antiretroviral drug granules, including lopinavir (LPV) ISNP granules and a fixed-dose combination of LPV/ritonavir (RTV) ISNP granules, were prepared using the ISNP nanotechnology, which spontaneously produced drug-loaded ISNPs in contact with water. Drug-loaded ISNPs had particle size less than 158nm with mono-dispersed distribution, over 95% entrapment efficiency for both LPV and RTV and stability over 8h in simulated physiological conditions. Drug-loaded ISNP granules with about 16% of LPV and 4% of RTV were palatable and stable at room temperature over 6months. Furthermore, LPV/RTV ISNP granules displayed a 2.56-fold increase in bioavailability and significantly increased LPV concentrations in tested tissues, especially in HIV sanctuary sites, as compared to the commercial LPV/RTV tablet (Kaletra®) in rats. Overall, the results demonstrated that the novel ISNP nanotechnology is a promising platform to manufacture palatable, "heat" stable, and flexible pediatric granules for fixed-dose combinations that can be used as sachets and sprinkles. To the best of our knowledge, this is the first report on this kind of novel nanotechnology for pediatric fixed-dose combinations of poorly water-soluble drugs.
Potent combination antiretroviral drug therapy has now been available to HIV-infected patients fo... more Potent combination antiretroviral drug therapy has now been available to HIV-infected patients for more than a decade, resulting in a significant decline in disease-related morbidity and mortality. Nonetheless, a number of HIV-infected individuals fail to experience the full benefit of their antiretroviral medications; some lack a robust virologic response, while others experience treatment-limiting toxicities. A number of factors may contribute to variable drug response in patients with HIV infection. Virologic, immunologic, pharmacologic, and pharmacokinetic differences between HIV-infected patients have all been noted to contribute to interpatient variability in drug response. Recent data suggest that pharmacogenetic differences among HIV-infected individuals may also be an important variable that contributes to antiretroviral drug response. Pharmacogenetic studies of antiretroviral drug therapy have explored the influence of single nucleotide polymorphisms in genes responsible f...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2006
Noninvasive imaging of a reporter gene is a new and promising technique to quantify transgene exp... more Noninvasive imaging of a reporter gene is a new and promising technique to quantify transgene expression after gene therapy. This study was performed to demonstrate visualization of lentiviral-marked cells by PET. We transduced nonhuman primate CD34+ hematopoietic cells with a lentiviral vector expressing a PET reporter gene, the mutant viral herpes simplex virus type 1-thymidine kinase (HSV1-sr39tk) gene. 1-(2-Fluoro-2-deoxy-beta-D-arabinofuranosyl)-76Br-5-bromouracil (76Br-FBAU) was used as the substrate for the viral tk enzyme. Upon phosphorylation, 76Br-FBAU was retained by cells and imaged by PET. The long half-life of 76Br, 16.2 h, permitted us to perform extended pharmacokinetic and imaging studies. 76Br-FBAU was retained in vascular tissues of the animals with transplanted tk lentiviral vector-transduced CD34+ cells. Elimination of 76Br-FBAU was through renal and hepatic excretion. Noninvasive molecular imaging using PET will help us, in the future, to define the contributio...
Background: Midazolam apparent oral clearance (CLORAL) is used to estimate intestinal and hepatic... more Background: Midazolam apparent oral clearance (CLORAL) is used to estimate intestinal and hepatic cytochrome P450 (CYP) 3A activity. A limited sampling approach was performed to access a midazolam partial area under the concentration time curve (AUC) to estimate CLORAL. Methods: Midazolam plasma concentrations from healthy adults were obtained during CYP3A baseline (n=116), inhibition (n=75), and induction or activation (n=66) from seven published studies. Observed CLORAL and partial AUCs of AUC0-2, AUC0-4, AUC0-6, AUC1-2, AUC1-4, AUC2-4, and AUC2-6 were determined by noncompartmental analysis. Subject data were randomly divided into a training set and a validation set. Linear regression equations, derived from partial AUCs, were developed from training set data. Predicted CLORAL was determined from these equations from validation set data. Preset criterion was a coefficient of determination (r 2) greater than or equal to 0.9. Bias and precision were evaluated by relative percent me...
Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in huma... more Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in humans by characterizing the effect of ritonavir on the pharmacokinetics of the P-gp substrate digoxin in individuals with known MDR1 genotypes. Healthy volunteers received a single dose of digoxin 0.4 mg orally before and after 14 days of ritonavir 200 mg twice daily. After each digoxin dose blood and urine were collected over 72 hours and analyzed for digoxin. Digoxin pharmacokinetic parameter values were determined using noncompartmental methods. MDR1 genotypes at positions 3435 and 2677 in exons 26 and 21, respectively, were determined using PCR-RFLP analysis. Ritonavir increased the digoxin AUC(0-72) from 26.20 +/- 8.67 to 31.96 +/- 11.24 ng x h/mL (P = 0.03) and the AUC(0-8) from 6.25 +/- 1.8 to 8.04 +/- 2.22 ng x h/mL (P = 0.02) in 12 subjects. Digoxin oral clearance decreased from 149 +/- 101 mL/h x kg to 105 +/- 57 mL/h x kg (P = 0.04). Other digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration. The majority of subjects were heterozygous at position 3435 (C/T) (6 subjects) and position 2677 (G/T,A) (7 subjects); although data are limited, the effect of ritonavir on digoxin pharmacokinetics appears to occur across all tested MDR1 genotypes. Concomitant low-dose ritonavir reduced the nonrenal clearance of digoxin, thereby increasing its systemic availability. The most likely mechanism for this interaction is ritonavir-associated inhibition of P-gp. Thus, ritonavir can alter the pharmacokinetics of coadministered medications that are P-gp substrates.
Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associat... more Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associated with abnormal serum lipoprotein concentrations. The purpose of this review is to describe serum lipid abnormalities related to protease inhibitor use. A MEDLINE search up to June 1, 1999, and abstracts from recent scientific meetings were primary data sources. Lipid disturbances in HIV-infected patients receiving protease inhibitors generally consist of elevated triglycerides and total cholesterol levels; HDL cholesterol is often reduced. The pathophysiological mechanism by which the protease inhibitors induce these lipid abnormalities has been hypothesized, but is unknown. Cases of pancreatitis and coronary heart disease have been described in hyperlipidemic patients receiving protease inhibitors. Treatment of protease inhibitor-related hyperlipidemia is unknown. Exchanging the offending protease inhibitor for nevirapine may be helpful in certain patients. Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of individuals.
To characterize amphotericin B-associated nephrotoxicity and to determine the variables associate... more To characterize amphotericin B-associated nephrotoxicity and to determine the variables associated with it that can be used to identify, a priori, at-risk patients. Retrospective analysis. University hospital. A homogeneous population of 69 recipients of a bone marrow (BMT) or peripheral blood stem cell transplant (PBSCT) with multiple myeloma and who received at least two doses of amphotericin B deoxycholate from January 1, 1992-January 1, 1995. Data on demographics, prior and concomitant nephrotoxic drug therapy, daily laboratory values, and amphotericin B dosing were collected serially from medical and pharmacy records. Forward stepwise logistic regression analysis was performed on the data from the first day of therapy to characterize and determine variables related to amphotericin B-associated nephrotoxicity. Nephrotoxicity occurred in 30 patients (43%) and developed rapidly Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline estimated creatinine clearance, cyclosporine therapy, nephrotoxic drug therapy within 30 days of starting amphotericin B, and the number of concomitant nephrotoxic drugs were significant predictors of amphotericin B-associated nephrotoxicity. Recipients of a BMT or PBSCT who have multiple myeloma and are receiving cyclosporine or multiple nephrotoxic drugs at the start of amphotericin B therapy should be considered at high risk for developing amphotericin B-associated nephrotoxicity. Also, because amphotericin B-associated nephrotoxicity develops rapidly, clinicians should be aware of the rapid changes in serum creatinine and electrolyte levels that can occur.
Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to vari... more Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open-label, three-period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single-strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration-time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir t(max) (1.87 [1.65-2.22] vs. 1.25 [1.03-1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small.
The Seville orange extract Citrus aurantium contains m‐synephrine (phenylephrine) and octopamine;... more The Seville orange extract Citrus aurantium contains m‐synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to “knock out” intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high‐performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 ± 0.52 μg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. In...
Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vin... more Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vinca alkaloid exposure and severe neurotoxicity. Recent reports of debilitating interactions between vincristine and itraconazole, as well as posaconazole, voriconazole and ketoconazole underscore the need to improve medical awareness of this adverse combination. We, therefore, undertook a comprehensive analysis of reports of adverse drug interactions (ADIs) with the combination of vincristine and azole antifungal agents, established a new classification, and provided a detailed summary of these toxicities. In patients who had sufficient data for analysis, 47 individuals were identified who had an ADI with the combination of vincristine and antifungal azoles. Median age was 8 years (1.3-68 years) with 33(70%) having a diagnosis of acute lymphoblastic leukaemia. Median time to ADI with vincristine was 9.5 days with itraconazole, 13.5 days posaconazole and 30 days voriconazole. The median nu...
Drug–drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in... more Drug–drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically‐based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2‐hour dose separation or dabigatran etex...
We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopri... more We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopristin, and eperezolid (formerly known as U-100,592) against four strains of enterococci. All regimens tested resulted in the growth inhibition of each isolate. Against the three clinafloxacin-susceptible strains, clinafloxacin tested alone was the most active treatment, decreasing the bacterial inoculum by more than 3 log10 CFU/ml after 24 h in time-kill curve studies.
The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of po... more The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of poorly water-soluble drugs in a children-friendly, flexible solid dosage form. For diseases like HIV, pediatric patients are taking multiple drugs for effective treatments. Fixed-dose combinations could reduce pill burdens and costs as well as improving patient adherence. However, development of fixed-dose combinations of poorly water-soluble drugs for pediatric formulations is very challenging. We discovered a novel nanotechnology that produced in situ self-assembly nanoparticles (ISNPs) when the ISNP granules were introduced to water. In this study, antiretroviral drug granules, including lopinavir (LPV) ISNP granules and a fixed-dose combination of LPV/ritonavir (RTV) ISNP granules, were prepared using the ISNP nanotechnology, which spontaneously produced drug-loaded ISNPs in contact with water. Drug-loaded ISNPs had particle size less than 158nm with mono-dispersed distribution, over 95% entrapment efficiency for both LPV and RTV and stability over 8h in simulated physiological conditions. Drug-loaded ISNP granules with about 16% of LPV and 4% of RTV were palatable and stable at room temperature over 6months. Furthermore, LPV/RTV ISNP granules displayed a 2.56-fold increase in bioavailability and significantly increased LPV concentrations in tested tissues, especially in HIV sanctuary sites, as compared to the commercial LPV/RTV tablet (Kaletra®) in rats. Overall, the results demonstrated that the novel ISNP nanotechnology is a promising platform to manufacture palatable, "heat" stable, and flexible pediatric granules for fixed-dose combinations that can be used as sachets and sprinkles. To the best of our knowledge, this is the first report on this kind of novel nanotechnology for pediatric fixed-dose combinations of poorly water-soluble drugs.
Potent combination antiretroviral drug therapy has now been available to HIV-infected patients fo... more Potent combination antiretroviral drug therapy has now been available to HIV-infected patients for more than a decade, resulting in a significant decline in disease-related morbidity and mortality. Nonetheless, a number of HIV-infected individuals fail to experience the full benefit of their antiretroviral medications; some lack a robust virologic response, while others experience treatment-limiting toxicities. A number of factors may contribute to variable drug response in patients with HIV infection. Virologic, immunologic, pharmacologic, and pharmacokinetic differences between HIV-infected patients have all been noted to contribute to interpatient variability in drug response. Recent data suggest that pharmacogenetic differences among HIV-infected individuals may also be an important variable that contributes to antiretroviral drug response. Pharmacogenetic studies of antiretroviral drug therapy have explored the influence of single nucleotide polymorphisms in genes responsible f...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2006
Noninvasive imaging of a reporter gene is a new and promising technique to quantify transgene exp... more Noninvasive imaging of a reporter gene is a new and promising technique to quantify transgene expression after gene therapy. This study was performed to demonstrate visualization of lentiviral-marked cells by PET. We transduced nonhuman primate CD34+ hematopoietic cells with a lentiviral vector expressing a PET reporter gene, the mutant viral herpes simplex virus type 1-thymidine kinase (HSV1-sr39tk) gene. 1-(2-Fluoro-2-deoxy-beta-D-arabinofuranosyl)-76Br-5-bromouracil (76Br-FBAU) was used as the substrate for the viral tk enzyme. Upon phosphorylation, 76Br-FBAU was retained by cells and imaged by PET. The long half-life of 76Br, 16.2 h, permitted us to perform extended pharmacokinetic and imaging studies. 76Br-FBAU was retained in vascular tissues of the animals with transplanted tk lentiviral vector-transduced CD34+ cells. Elimination of 76Br-FBAU was through renal and hepatic excretion. Noninvasive molecular imaging using PET will help us, in the future, to define the contributio...
Background: Midazolam apparent oral clearance (CLORAL) is used to estimate intestinal and hepatic... more Background: Midazolam apparent oral clearance (CLORAL) is used to estimate intestinal and hepatic cytochrome P450 (CYP) 3A activity. A limited sampling approach was performed to access a midazolam partial area under the concentration time curve (AUC) to estimate CLORAL. Methods: Midazolam plasma concentrations from healthy adults were obtained during CYP3A baseline (n=116), inhibition (n=75), and induction or activation (n=66) from seven published studies. Observed CLORAL and partial AUCs of AUC0-2, AUC0-4, AUC0-6, AUC1-2, AUC1-4, AUC2-4, and AUC2-6 were determined by noncompartmental analysis. Subject data were randomly divided into a training set and a validation set. Linear regression equations, derived from partial AUCs, were developed from training set data. Predicted CLORAL was determined from these equations from validation set data. Preset criterion was a coefficient of determination (r 2) greater than or equal to 0.9. Bias and precision were evaluated by relative percent me...
Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in huma... more Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in humans by characterizing the effect of ritonavir on the pharmacokinetics of the P-gp substrate digoxin in individuals with known MDR1 genotypes. Healthy volunteers received a single dose of digoxin 0.4 mg orally before and after 14 days of ritonavir 200 mg twice daily. After each digoxin dose blood and urine were collected over 72 hours and analyzed for digoxin. Digoxin pharmacokinetic parameter values were determined using noncompartmental methods. MDR1 genotypes at positions 3435 and 2677 in exons 26 and 21, respectively, were determined using PCR-RFLP analysis. Ritonavir increased the digoxin AUC(0-72) from 26.20 +/- 8.67 to 31.96 +/- 11.24 ng x h/mL (P = 0.03) and the AUC(0-8) from 6.25 +/- 1.8 to 8.04 +/- 2.22 ng x h/mL (P = 0.02) in 12 subjects. Digoxin oral clearance decreased from 149 +/- 101 mL/h x kg to 105 +/- 57 mL/h x kg (P = 0.04). Other digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration. The majority of subjects were heterozygous at position 3435 (C/T) (6 subjects) and position 2677 (G/T,A) (7 subjects); although data are limited, the effect of ritonavir on digoxin pharmacokinetics appears to occur across all tested MDR1 genotypes. Concomitant low-dose ritonavir reduced the nonrenal clearance of digoxin, thereby increasing its systemic availability. The most likely mechanism for this interaction is ritonavir-associated inhibition of P-gp. Thus, ritonavir can alter the pharmacokinetics of coadministered medications that are P-gp substrates.
Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associat... more Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associated with abnormal serum lipoprotein concentrations. The purpose of this review is to describe serum lipid abnormalities related to protease inhibitor use. A MEDLINE search up to June 1, 1999, and abstracts from recent scientific meetings were primary data sources. Lipid disturbances in HIV-infected patients receiving protease inhibitors generally consist of elevated triglycerides and total cholesterol levels; HDL cholesterol is often reduced. The pathophysiological mechanism by which the protease inhibitors induce these lipid abnormalities has been hypothesized, but is unknown. Cases of pancreatitis and coronary heart disease have been described in hyperlipidemic patients receiving protease inhibitors. Treatment of protease inhibitor-related hyperlipidemia is unknown. Exchanging the offending protease inhibitor for nevirapine may be helpful in certain patients. Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of individuals.
To characterize amphotericin B-associated nephrotoxicity and to determine the variables associate... more To characterize amphotericin B-associated nephrotoxicity and to determine the variables associated with it that can be used to identify, a priori, at-risk patients. Retrospective analysis. University hospital. A homogeneous population of 69 recipients of a bone marrow (BMT) or peripheral blood stem cell transplant (PBSCT) with multiple myeloma and who received at least two doses of amphotericin B deoxycholate from January 1, 1992-January 1, 1995. Data on demographics, prior and concomitant nephrotoxic drug therapy, daily laboratory values, and amphotericin B dosing were collected serially from medical and pharmacy records. Forward stepwise logistic regression analysis was performed on the data from the first day of therapy to characterize and determine variables related to amphotericin B-associated nephrotoxicity. Nephrotoxicity occurred in 30 patients (43%) and developed rapidly Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline estimated creatinine clearance, cyclosporine therapy, nephrotoxic drug therapy within 30 days of starting amphotericin B, and the number of concomitant nephrotoxic drugs were significant predictors of amphotericin B-associated nephrotoxicity. Recipients of a BMT or PBSCT who have multiple myeloma and are receiving cyclosporine or multiple nephrotoxic drugs at the start of amphotericin B therapy should be considered at high risk for developing amphotericin B-associated nephrotoxicity. Also, because amphotericin B-associated nephrotoxicity develops rapidly, clinicians should be aware of the rapid changes in serum creatinine and electrolyte levels that can occur.
Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to vari... more Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open-label, three-period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single-strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration-time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir t(max) (1.87 [1.65-2.22] vs. 1.25 [1.03-1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small.
The Seville orange extract Citrus aurantium contains m‐synephrine (phenylephrine) and octopamine;... more The Seville orange extract Citrus aurantium contains m‐synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to “knock out” intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high‐performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 ± 0.52 μg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. In...
Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vin... more Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vinca alkaloid exposure and severe neurotoxicity. Recent reports of debilitating interactions between vincristine and itraconazole, as well as posaconazole, voriconazole and ketoconazole underscore the need to improve medical awareness of this adverse combination. We, therefore, undertook a comprehensive analysis of reports of adverse drug interactions (ADIs) with the combination of vincristine and azole antifungal agents, established a new classification, and provided a detailed summary of these toxicities. In patients who had sufficient data for analysis, 47 individuals were identified who had an ADI with the combination of vincristine and antifungal azoles. Median age was 8 years (1.3-68 years) with 33(70%) having a diagnosis of acute lymphoblastic leukaemia. Median time to ADI with vincristine was 9.5 days with itraconazole, 13.5 days posaconazole and 30 days voriconazole. The median nu...
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Papers by Scott Penzak