JACCP: JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY, 2019
Clinical pharmacists have been incorporating precision medicine into practice for decades. Drug s... more Clinical pharmacists have been incorporating precision medicine into practice for decades. Drug selection and dosing based on patient‐specific clinical factors such as age, weight, renal function, drug interactions, plasma drug concentrations, and diet are expected as part of routine clinical practice. Newer concepts of precision medicine such as pharmacogenomics have recently been implemented into clinical care, while other concepts such as epigenetics and pharmacomicrobiomics still predominantly exist in the research area but clinical translation is expected in the future. The purpose of this paper is to describe current and emerging aspects of precision medicine as it relates to clinical pharmacy across a variety of specialty areas of practice, with perspectives from the American College of Clinical Pharmacy Practice and Research Network membership.
Complications throughout the peripartum period may be caused by preexisting conditions or pregnan... more Complications throughout the peripartum period may be caused by preexisting conditions or pregnancy-induced conditions and may alter pharmacotherapy management. Pharmacotherapy management during late pregnancy and delivery requires careful consideration due to changing hormones, hemodynamic status, and pharmacokinetics, and concerns for potential maternal and/or fetal morbidity. Increased maternal and fetal monitoring are often required and may lead to therapy changes. Pharmacists, as key members of the interprofessional team, can contribute essential perspective to the management of postpartum pharmacotherapy through assessment and recommendation of appropriate and judicious use of medications.
The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated i... more The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty‐seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3‐hydroxymorphinan (3HM), were determined from a 2‐hour post‐dose plasma sample and cumulative 4‐hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 act...
OBJECTIVE: To describe a patient with increased tacrolimus concentrations due to a diltiazem drug... more OBJECTIVE: To describe a patient with increased tacrolimus concentrations due to a diltiazem drug interaction. CASE SUMMARY: A 68-year-old white man, four months following orthotopic liver transplantation secondary to hepatitis C and Laënnec's cirrhosis, was admitted to the intensive care unit for diarrhea, dehydration, and atrial fibrillation. He was stabilized on oral tacrolimus 8 mg twice daily, with a whole blood tacrolimus trough concentration of 12.9 ng/mL on admission. He was started on a continuous infusion of diltiazem for one day, followed by 30 mg orally every eight hours. Three days after admission, the patient became delirious, confused, and agitated; he was found to have a whole blood tacrolimus trough concentration of 55 ng/mL. The tacrolimus was withheld and diltiazem was discontinued. The tacrolimus concentrations fell over the next three days to 6.7 ng/mL, with a corresponding improvement in his mental status. The oral tacrolimus was restarted at 3 mg twice dai...
Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplanta... more Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P-glycoprotein. A pharmacokinetic interaction between St. John's wort (antidepressant herbal product and inducer of CYP3A and P-glycoprotein) and tacrolimus was evaluated in 10 healthy volunteers. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected following single oral doses (0.1 mg/kg) prior to and during an 18-day concomitant St. John's wort dosing phase (300 mg orally three times daily). Coadministration of St. John's wort significantly decreased tacrolimus AUC (306.9 microg.h/L +/- 175.8 microg.h/L vs. 198.7 microg.h/L +/- 139.6 microg.h/L; p=0.004) and increased apparent oral clearance (349.0 mL/h/kg +/- 126.0 mL/h/kg vs. 586.4 mL/h/kg +/- 274.9 mL/h/kg; p=0.01) and apparent oral volume of distribution at steady state (11.5 L/kg +/- 4.3 L/kg vs. 17.6 L/kg +/- 9.6 L/kg; p=0.04). St. John's wort appears to induce tacrolimus metabolism, most likely through induction of CYP3A and P-glycoprotein.
Limited data are available on the effects of pregnancy on the maternal metabolome. Therefore, the... more Limited data are available on the effects of pregnancy on the maternal metabolome. Therefore, the objective of this study was to use metabolomics analysis to determine pathways impacted by pregnancy followed by targeted confirmatory analysis to provide more powerful conclusions about metabolic alterations during pregnancy. Forty-seven pregnant women, 18–50 years of age were included in this study, with each subject serving as their own control. Plasma samples were collected between 25 and 28 weeks gestation and again ≥3 months postpartum for metabolomics analysis utilizing an HILIC/UHPLC/MS/MS assay with confirmatory targeted specific concentration analysis for 10 of the significantly altered amino acids utilizing an LC/MS assay. Principle component analysis (PCA) on metabolomics data clearly separated pregnant and postpartum groups and identified outliers in a preliminary assessment. Of the 980 metabolites recorded, 706 were determined to be significantly different between pregnanc...
Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known abou... more Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (n = 23) during two stages of pregnancy (25–28 weeks gestation and 28–32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25–28 weeks gestation, plasma retinol (−27%), 4-oxo-13-cis-retinoic acid (−34%), and albumin (−22%) concentrations were significantly lower, and all-trans-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28–32 weeks gestation, plasma retinol (−41%), retinol binding protein 4 (RBP4; −17%), tr...
Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catec... more Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.
In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin ... more In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β‐cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed‐meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β‐cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β‐cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.
JACCP: JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY, 2019
Clinical pharmacists have been incorporating precision medicine into practice for decades. Drug s... more Clinical pharmacists have been incorporating precision medicine into practice for decades. Drug selection and dosing based on patient‐specific clinical factors such as age, weight, renal function, drug interactions, plasma drug concentrations, and diet are expected as part of routine clinical practice. Newer concepts of precision medicine such as pharmacogenomics have recently been implemented into clinical care, while other concepts such as epigenetics and pharmacomicrobiomics still predominantly exist in the research area but clinical translation is expected in the future. The purpose of this paper is to describe current and emerging aspects of precision medicine as it relates to clinical pharmacy across a variety of specialty areas of practice, with perspectives from the American College of Clinical Pharmacy Practice and Research Network membership.
Complications throughout the peripartum period may be caused by preexisting conditions or pregnan... more Complications throughout the peripartum period may be caused by preexisting conditions or pregnancy-induced conditions and may alter pharmacotherapy management. Pharmacotherapy management during late pregnancy and delivery requires careful consideration due to changing hormones, hemodynamic status, and pharmacokinetics, and concerns for potential maternal and/or fetal morbidity. Increased maternal and fetal monitoring are often required and may lead to therapy changes. Pharmacists, as key members of the interprofessional team, can contribute essential perspective to the management of postpartum pharmacotherapy through assessment and recommendation of appropriate and judicious use of medications.
The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated i... more The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty‐seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3‐hydroxymorphinan (3HM), were determined from a 2‐hour post‐dose plasma sample and cumulative 4‐hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 act...
OBJECTIVE: To describe a patient with increased tacrolimus concentrations due to a diltiazem drug... more OBJECTIVE: To describe a patient with increased tacrolimus concentrations due to a diltiazem drug interaction. CASE SUMMARY: A 68-year-old white man, four months following orthotopic liver transplantation secondary to hepatitis C and Laënnec's cirrhosis, was admitted to the intensive care unit for diarrhea, dehydration, and atrial fibrillation. He was stabilized on oral tacrolimus 8 mg twice daily, with a whole blood tacrolimus trough concentration of 12.9 ng/mL on admission. He was started on a continuous infusion of diltiazem for one day, followed by 30 mg orally every eight hours. Three days after admission, the patient became delirious, confused, and agitated; he was found to have a whole blood tacrolimus trough concentration of 55 ng/mL. The tacrolimus was withheld and diltiazem was discontinued. The tacrolimus concentrations fell over the next three days to 6.7 ng/mL, with a corresponding improvement in his mental status. The oral tacrolimus was restarted at 3 mg twice dai...
Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplanta... more Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P-glycoprotein. A pharmacokinetic interaction between St. John's wort (antidepressant herbal product and inducer of CYP3A and P-glycoprotein) and tacrolimus was evaluated in 10 healthy volunteers. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected following single oral doses (0.1 mg/kg) prior to and during an 18-day concomitant St. John's wort dosing phase (300 mg orally three times daily). Coadministration of St. John's wort significantly decreased tacrolimus AUC (306.9 microg.h/L +/- 175.8 microg.h/L vs. 198.7 microg.h/L +/- 139.6 microg.h/L; p=0.004) and increased apparent oral clearance (349.0 mL/h/kg +/- 126.0 mL/h/kg vs. 586.4 mL/h/kg +/- 274.9 mL/h/kg; p=0.01) and apparent oral volume of distribution at steady state (11.5 L/kg +/- 4.3 L/kg vs. 17.6 L/kg +/- 9.6 L/kg; p=0.04). St. John's wort appears to induce tacrolimus metabolism, most likely through induction of CYP3A and P-glycoprotein.
Limited data are available on the effects of pregnancy on the maternal metabolome. Therefore, the... more Limited data are available on the effects of pregnancy on the maternal metabolome. Therefore, the objective of this study was to use metabolomics analysis to determine pathways impacted by pregnancy followed by targeted confirmatory analysis to provide more powerful conclusions about metabolic alterations during pregnancy. Forty-seven pregnant women, 18–50 years of age were included in this study, with each subject serving as their own control. Plasma samples were collected between 25 and 28 weeks gestation and again ≥3 months postpartum for metabolomics analysis utilizing an HILIC/UHPLC/MS/MS assay with confirmatory targeted specific concentration analysis for 10 of the significantly altered amino acids utilizing an LC/MS assay. Principle component analysis (PCA) on metabolomics data clearly separated pregnant and postpartum groups and identified outliers in a preliminary assessment. Of the 980 metabolites recorded, 706 were determined to be significantly different between pregnanc...
Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known abou... more Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (n = 23) during two stages of pregnancy (25–28 weeks gestation and 28–32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25–28 weeks gestation, plasma retinol (−27%), 4-oxo-13-cis-retinoic acid (−34%), and albumin (−22%) concentrations were significantly lower, and all-trans-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28–32 weeks gestation, plasma retinol (−41%), retinol binding protein 4 (RBP4; −17%), tr...
Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catec... more Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.
In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin ... more In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β‐cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed‐meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β‐cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β‐cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.
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