The Journal of Clinical Pharmacology (J CLIN PHARMACOL)

Publications in this journal

• Article: The Predictive Value of the In Vitro Platelet Toxicity Assay (iPTA) for the Diagnosis of Hypersensitivity Reactions to Sulfonamides.

  Abdelbaset A Elzagallaai, Gideon Koren, Michael J Rieder
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  ABSTRACT: Drug hypersensitivity reactions (DHRs) are rare but potentially fatal adverse drug reactions (ADRs). A reliable test to diagnose DHRs would be a major advance in the clinical care for patients and in the evaluation of ADRs during drug development as well as for mechanistic studies of drug hypersensitivity. Available in vitro tests including the lymphocyte toxicity assay (LTA) have been used but are time-consuming, cumbersome, and expensive. We have developed a novel diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA). The aim of this study was to evaluate the predictive value of the iPTA in diagnosis of DHRs to sulfonamides. We recruited 66 individuals (36 DHS-sulfa patients and 30 healthy controls) to participate in the study. Blood samples were obtained and LTA and iPTA were performed in parallel. There was concentration-dependent toxicity in the cells of patients when incubated with the reactive hydroxylamine metabolite of sulfamethoxazole for both the LTA and iPTA (P < .05). The iPTA was more sensitive than conventional LTA test in detecting susceptibility of patient cells to in vitro toxicity (P < .05). The novel iPTA has considerable potential as an investigative tool for DHS as it is more sensitive and cheaper, requiring no special reagents.
  The Journal of Clinical Pharmacology 05/2013;
• Article: Effects of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes and an Inhibitor of OATP1B1/3 Transport, on the Single Dose Pharmacokinetics of Anacetrapib.

  Matt S Anderson, Josee Cote, Yang Liu, Daria Stypinski, Patrice Auger, Anne Hohnstein, Scott Rasmussen, Amy O Johnson-Levonas, David E Gutstein
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  ABSTRACT: Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
  The Journal of Clinical Pharmacology 05/2013;
• Article: Pharmacokinetics of Immunomodulator Treatments After Roux-En-Y Bypass in Obese Patient.

  Judith Aron-Wisnewsky, Florian Lemaitre, Karine Clément, Jean-Luc Bouillot, Christine Fernandez, Arnaud Basdevant, Jean-Michel Oppert, Marion Buyse
  The Journal of Clinical Pharmacology 05/2013;
• Article: Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus.

  Damayanthi Devineni, Christopher R Curtin, David Polidori, Maria J Gutierrez, Joseph Murphy, Sarah Rusch, Paul L Rothenberg
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  ABSTRACT: This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG ], urinary glucose excretion [UGE0-24h ], and 24-hour mean plasma glucose [MPG0-24h ]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax ) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady-state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose- and exposure-dependent. All canagliflozin doses decreased RTG , increased UGE0-24h , and reduced MPG0-24h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG0-24h ranged from 42-57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen.
  The Journal of Clinical Pharmacology 05/2013;
• Article: Localization of Scopolamine Induced Electrocortical Brain Activity Changes, in Healthy Humans at Rest.

  Pedro Miguel Ramos Reis, Holger Eckhardt, Pierre Denise, Friedrich Bodem, Matthias Lochmann
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  ABSTRACT: To prevent the participants of parabolic flights from nausea they are optionally treated with subcutaneously injected antiemetic scopolamine. The range of side effects of this substance include reductions of the α-2 frequency band. Previous studies, however, have given no information as to which generator centers are responsible for this effect. The objective of this study therefore, is to identify the cortex area that may be responsible for this effect. Six participants were subcutaneously administered 0.7 mg of scopolamine. EEG was recorded for 10 minutes before to 20 minutes after injection. Data preprocessing followed including filtering and artifact minimization. A statistical analysis was performed with sLORETA/eLORETA software for each subject over a time window from 3 minutes before to 17-20 minutes after scopolamine injection. Results show, that in the BA7, the precuneus, on both hemispheres suffered a α-2 activity decrease in absolute power. The identified brain cortex center is an important hub with high connectivity and centrality values within the neural network. It contributes to the control of movement and to space orientation. Therefore, an activity alteration in this area can possibly explain the antiemetic effect of scopolamine and open a window to understand the origin of motion sickness.
  The Journal of Clinical Pharmacology 05/2013;
• Article: Brivaracetam Disposition in Mild to Severe Hepatic Impairment.

  Armel Stockis, Maria Laura Sargentini-Maier, Yves Horsmans
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  ABSTRACT: Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand in clinical development for epilepsy. This open-label, single-dose study evaluated brivaracetam disposition in participants with different degrees of hepatic impairment versus matched healthy controls. Twenty-six participants (38-72 years; 19 males and 7 females) with hepatic impairment classified by Child-Pugh score (mild, n = 6; moderate, n = 7; severe, n = 7) or normal hepatic function (n = 6) received a single oral dose of 100 mg brivaracetam. The pharmacokinetics of brivaracetam and its three main metabolites (acid, hydroxy, hydroxyacid) were determined and correlated with impairment severity. Dynamic liver function tests correlated with hepatic impairment severity. The plasma half-life of brivaracetam was 9.8, 14.2, 16.4, and 17.4 hours and the area under the plasma concentration-time curve was 29.7, 44.6, 46.7, and 47.1 µg h/mL in healthy controls and participants with mild, moderate, and severe liver impairment, respectively. Production of the acid metabolite was increased and the hydroxylated metabolites were decreased in participants with hepatic impairment versus healthy controls. Exposure to brivaracetam increased by 50-60% in patients with hepatic impairment, irrespective of severity. The relative importance of biotransformation pathways was altered; cytochrome P450 (CYP)-dependent hydroxylation decreased; CYP-independent acid metabolite formation increased concomitantly.
  The Journal of Clinical Pharmacology 05/2013;
• Article: A Model-Based Approach to Predict Longitudinal HbA1c, Using Early Phase Glucose Data From Type 2 Diabetes Mellitus Patients After Anti-Diabetic Treatment.

  Maria C Kjellsson, Valérie F Cosson, Norman A Mazer, Nicolas Frey, Mats O Karlsson
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  ABSTRACT: Predicting late phase outcomes from early-phase findings can help inform decisions in drug development. If the measurements in early-phase differ from those in late phase, forecasting is more challenging. In this paper, we present a model-based approach for predicting glycosylated hemoglobin (HbA1c) in late phase using glucose and insulin concentrations from an early-phase study, investigating an anti-diabetic treatment. Two previously published models were used; an integrated glucose and insulin (IGI) model for meal tolerance tests and an integrated glucose-red blood cell-HbA1c (IGRH) model predicting the formation of HbA1c from the average glucose concentration (Cg,av ). Output from the IGI model was used as input to the IGRH model. Parameters of the IGI model and drug effects were estimated using data from a phase1 study in 59 diabetic patients receiving various doses of a glucokinase activator. Cg,av values were simulated according to a Phase 2 study design and used in the IGRH model for predictions of HbA1c. The performance of the model-based approach was assessed by comparing the predicted to the actual outcome of the Phase 2 study. We have shown that this approach well predicts the longitudinal HbA1c response in a 12-week study using only information from a 1-week study where glucose and insulin concentrations were measured.
  The Journal of Clinical Pharmacology 04/2013;
• Article: Ranolazine in Heart Failure With Preserved Left Ventricular Ejection Fraction and Microvascular Dysfunction: Case Report and Literature Review.

  Emilia D'Elia, Luigi Fiocca, Paolo Ferrero, Attilio Iacovoni, Pierangelo Baio, Giuseppe Medolago, Vincenzo Duino, Mauro Gori, Antonello Gavazzi, Michele Senni
  The Journal of Clinical Pharmacology 04/2013;
• Article: Time-Dependent Inhibition and Induction of Human Cytochrome P4503A4/5 by an Oral IAP Antagonist, LCL161, In Vitro and In Vivo in Healthy Subjects.

  Shyeilla Dhuria, Heidi Einolf, James Mangold, Suman Sen, Helen Gu, Lai Wang, Scott Cameron
  The Journal of Clinical Pharmacology 04/2013;
• Article: Incorporation of 6-Thioguanine Nucleotides into DNA During Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia-The Influence of Thiopurine Methyltransferase Genotypes.

  Maria S Ebbesen, Jacob Nersting, Jack H Jacobsen, Thomas L Frandsen, Kim Vettenranta, Jonas Abramsson, Finn Wesenberg, Kjeld Schmiegelow
  The Journal of Clinical Pharmacology 04/2013;
• Article: Tako-Tsubo Cardiomyopathy Following Modafinil Use.

  Desiree Marie Younes, Federico Asch
  The Journal of Clinical Pharmacology 03/2013;
• Article: Aerosol Particle Size Does Not Predict Pharmacokinetic Determined Lung Dose in Children.

  Klaus Bønnelykke, Bo L K Chawes, Signe Vindfeld, Alison C Moore, Hans Bisgaard
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  ABSTRACT: In vitro measures of aerosol particles size, such as the fine particle mass, play a pivotal role for approval of inhaled anti-asthmatic drugs. However, the validity as a measure of dose to the lungs in children lacks evidence. In this study we investigated for the first time the association between an in vivo estimate of lung dose of inhaled drug in children and the corresponding particle size segments assessed ex vivo. Lung dose of fluticasone propionate after inhalation from a dry powder inhaler (Diskus®) was studied in 23 children aged 4-7 and 12-15 years with mild asthma. Six-hour pharmacokinetics was assessed after single inhalation. The corresponding emitted mass of drug in segments of aerosol particle size was assessed ex vivo by replicating the inhalation flows recorded by transducers built into the Diskus® inhaler and re-playing them in a breathing simulator. There was no correlation between any inhaled particle size segment and lung dose assessed by pharmacokinetics and adjusted for age and body size. Measures of particles size segments were not related to lung dose in children. Until further evidence is provided it may be warranted to emphasize pharmacokinetic or pharmacodynamic assessments of drug delivery to the lung.
  The Journal of Clinical Pharmacology 03/2013;
• Article: Impact of Sildenafil on Survival of Patients With Eisenmenger Syndrome.

  Yun-Juan Sun, Tao Yang, Wei-Jie Zeng, Qing Gu, Xin-Hai Ni, Zhi-Hui Zhao, Zhi-Hong Liu, Chang-Ming Xiong, Jian-Guo He
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  ABSTRACT: The favorable effects of short-term use of sildenafil on patients with Eisenmenger syndrome have been reported. We further studied the impact of long-term use of sildenafil on survival of these patients. In this study, the baseline data of patients newly diagnosed as Eisenmenger syndrome in our hospital between January 2005 and December 2009 were retrospectively collected. Patients were followed-up either by telephone contacts or during visits in our out-patient clinic. A total of 121 patients (68 patients in conventional group and 53 patients in sildenafil group) were finally included and 29 patients were re-evaluated after sildenafil therapy for 3-4 months. Compared with the baseline, a 6-minute walk distance, functional classes, plasma hemoglobin level, and hemodynamics were significantly improved after sildenafil treatment. During a median follow-up period of 35.8 months, 15 patients died (11 patients in conventional group). The 1- and 3-year survival rates in sildenafil group were 97.0% and 95.2%, significantly higher than 90.6% and 82.9% in conventional group P = .025). Multivariate analysis showed that sildenafil therapy, functional class and mean pulmonary arterial pressure were independently associated with survival. Therefore, long-term sildenafil therapy improved survival in patients with Eisenmenger syndrome.
  The Journal of Clinical Pharmacology 03/2013;
• Article: Incidence and Costs of Adverse Drug Reactions in a Tertiary Care Pediatric Intensive Care Unit.

  Wei Du, Victoria Tutag Lehr, Mary Caverly, Lauren Kelm, Jaxk Reeves, Mary Lieh-Lai
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  ABSTRACT: Adverse drug reactions (ADRs) increase morbidity, mortality, and hospital costs in children treated in the Pediatric Intensive Care Unit (PICU). Few studies have reported the incidence and risk factors of ADRs in PICU. Our study aimed to evaluate incidence, risk factors, and economic burden of ADRs in PICU. An intensive ADR surveillance was conducted at the PICU of Children's Hospital of Michigan between November 1, 2010 and May 31, 2011. A trigger list was used to screen for suspected ADR cases. Of the 697 consecutive PICU admissions reviewed, 13.1% experienced at least one episode of ADR. The ADR incidence was 22% in patients with cardiovascular (CV) surgery and 11.5% in other patients. The most frequently detected ADR was electrolyte imbalance associated with diuretic exposure. Mean age at admission was 4 years (interquartile range: 9 months-13 years). Risk factors for ADR included young age (<1 year), Pediatric Risk of Mortality (PRISM) score upon admission ≥3, and administration of ≥16 medications. ADRs increased total ICU costs by 3.5-fold and length of ICU stay by 3.8-fold. Increased ADR surveillance of high risk patients in conjunction with early intervention may reduce drug related morbidity and costs in the PICU.
  The Journal of Clinical Pharmacology 03/2013;
• Article: Axitinib in Metastatic Renal Cell Carcinoma: Results of a Pharmacokinetic and Pharmacodynamic Analysis.

  Brian I Rini, May Garrett, Bill Poland, Janice P Dutcher, Olivier Rixe, George Wilding, Walter M Stadler, Yazdi K Pithavala, Sinil Kim, Jamal Tarazi, Robert J Motzer
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  ABSTRACT: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc ) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.
  The Journal of Clinical Pharmacology 03/2013;
• Article: The antibody drug absorption following subcutaneous or intramuscular administration and its mathematical description by coupling physiologically based absorption process with the conventional compartment pharmacokinetic model.

  Liang Zhao, Ping Ji, Zhihong Li, Partha Roy, Chandrahas G Sahajwalla
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  ABSTRACT: The main objective of this paper is to propose a quantitative model to describe the absorption process for monoclonal antibody (mAb) following subcutaneous (SC) or intramuscular (IM) administration. A hybrid model was established by coupling the physiologically based absorption process with a conventional pharmacokinetic-pharmacodynamic (PK-PD) or PK model associated with intravenous infusion. Key physiological parameters evaluated include the volume distribution before systemic absorption, mAb drug clearance during lymphatic transport, the neonatal Fc receptor (FcRn) capacity, the intrinsic drug clearance via lysosomal proteolytic process, and the lymphatic flow rate. Sensitivity analyses were performed to identify those physiological parameters significantly impacting time to peak concentration (T(max) ) or drug bioavailability. Simulation results showed that lymphatic flow rate is the only influential factor to T(max) . Lymphatic transit time and drug clearance during lymphatic transport are most influential to bioavailability but not identifiable in their effects. Bioavailability is positively related to the lymphatic flow only at its low range (i.e., at <0.5-fold of the selected value of 0.043 mL/min). The rest of physiological parameters only have marginal effects on either drug bioavailability or T(max) . Finally, simulation results confirmed lymphatic transport as the major route of mAb delivery.
  The Journal of Clinical Pharmacology 03/2013; 53(3):314-25.
• Article: Population pharmacokinetics of unbound and total drug concentrations following intravenously administered carbamazepine in elderly and younger adult patients with epilepsy.

  Ghada F Ahmed, Richard C Brundage, Susan E Marino, James C Cloyd, Ilo E Leppik, Page B Pennell, R Eugene Ramsay, Angela K Birnbaum
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  ABSTRACT: The objective of the study was to investigate the pharmacokinetics (PK) of unbound and total plasma carbamazepine (CBZ) concentrations following simultaneous administration of intravenous and oral formulations. We tested the hypothesis that age-related alterations in physiology and patient characteristics influence CBZ disposition and protein binding. Patients (n = 113) on maintenance therapy received a 100 mg dose of a novel, intravenous, stable-labeled (SL) CBZ formulation as partial replacement of their morning CBZ dose. A two-compartment model described unbound and total SL-CBZ data. The stable-labeled intravenous dosing methodology enabled the estimation of the CBZ clearance (CL) and volumes of distribution. The CL of CBZ was dependent on race through the model equation unbound CL (L/hour) = 11.2 × (1.30)(Race) ; where Race = 1 for Caucasian, 0 for African American. Total body weight explained 57% and 70% of the interindividual variability in the central and peripheral volumes of distribution, respectively. Age, sex, smoking, plasma albumin, and alpha 1-acid glycoprotein concentrations had no effect on CL, binding or volumes of distribution. The model was evaluated via bootstrap and predictive check. Results may support race specific dosing for CBZ where an average African-American individual would receive 70% of the standard dose prescribed for the Caucasian person.
  The Journal of Clinical Pharmacology 03/2013; 53(3):276-84.
• Article: Population Pharmacokinetic Analysis of a Nevirapine-Based HIV-1 Prevention of Mother-to-Child Transmission Program in Uganda to Assess the Impact of Different Dosing Regimens for Newborns.

  Monika Frank, Gundel Harms, Andrea Kunz, Charlotte Kloft
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  ABSTRACT: Single-dose nevirapine for mothers and newborns at delivery is the simplest prevention strategy for vertical HIV-1 transmission and hence widely used in resource-constrained settings. HIV-1-positive mothers and newborns received single-dose nevirapine in a prevention of mother-to-child HIV-1 transmission (PMTCT) program in Uganda. In a pharmacokinetic investigation, breast milk and plasma samples of mothers and newborns were collected. The nonlinear mixed-effects modeling approach was suitable for analysis (average: 1.8 samples/matrix/individual). For describing the nevirapine pharmacokinetics in mothers and newborns, a 1-compartment model was demonstrated to be sufficient. The plasma-placenta transfer could be quantified, revealing a transfer fraction of 11% to 25% (with a significant influence of time span between maternal nevirapine intake and birth) and a high transfer rate constant from maternal drug administration. Interindividual variability was moderate between mothers and high between newborns. Simulations revealed that newborns born early (<1 hour) after maternal nevirapine intake would benefit from a 3-fold higher nevirapine dosage (6 mg/kg) after birth for analogous protective plasma concentrations over the first 2 weeks. In contrast, postnatal nevirapine dosage seemed to be dispensable for newborns born late (>24 hours) after maternal nevirapine intake. These dosing recommendations should be evaluated in prospective studies, including additional antiretroviral drugs in accordance with current PMTCT guidelines.
  The Journal of Clinical Pharmacology 03/2013; 53(3):294-304.
• Article: Comparing the pharmacokinetics of doxylamine/pyridoxine delayed-release combination in nonpregnant women of reproductive age and women in the first trimester of pregnancy.

  Ilan Matok, Shannon Clark, Steve Caritis, Menachem Miodovnik, Jason Umans, Gary Hankins, Gideon Koren
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  ABSTRACT: Although Diclectin (doxylamine/pyridoxine delayed-released combination) is widely used in Canada, its pharmacokinetics (PK) during pregnancy has never been described. The objective of this study was to compare the PK of doxylamine/pyridoxine delayed-released combination in pregnant versus nonpregnant women. The apparent clearances (CL) of doxylamine and pyridoxal 5'-phosphate (PLP; the active metabolite of vitamin B(6) ) during the first-trimester pregnancy in women who participated in a Diclectin randomized trial were compared with those of healthy, adult, nonpregnant women who participated in a voluntary PK trial. Eighteen nonpregnant women were compared with 50 pregnant women who were treated with Diclectin. There was no difference in the apparent CL of doxylamine in women in their first trimester of pregnancy when compared with nonpregnant women on day 4 (median = 196.7 vs 249.5 mL/h/kg, respectively, P = .065), day 8 (median = 248.4 vs 249.5 mL/h/kg, respectively, P = .82), and day 15 (median = 200.9 vs 249.5 mL/h/kg, respectively, P = .55). No difference was found in the apparent CL of PLP on day 15 (median = 342.3 vs 314.7 mL/h/kg, respectively, P = .92). There was no pregnancy-induced effect in the apparent CL of either doxylamine or PLP in women during the first trimester of pregnancy despite the existence of morning sickness.
  The Journal of Clinical Pharmacology 03/2013; 53(3):334-8.