John N van den Anker

Publications (13)45 Total impact

• Article: Pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus.

  James M Chamberlain, Edmund V Capparelli, Kathleen M Brown, Cheryl W Vance, Kathleen Lillis, Prashant Mahajan, Richard Lichenstein, Rachel M Stanley, Colleen O Davis, Stephen Gordon, Jill M Baren, John N van den Anker
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  ABSTRACT: To evaluate the single dose pharmacokinetics of an intravenous dose of lorazepam in pediatric patients treated for status epilepticus (SE) or with a history of SE. Ten hospitals in the Pediatric Emergency Care Applied Research Network enlisted patients 3 months to 17 years with convulsive SE (status cohort) or for a traditional pharmacokinetics study (elective cohort). Sparse sampling was used for the status cohort, and intensive sampling was used for the elective cohort. Non-compartmental analyses were performed on the elective cohort, and served to nest compartmental population pharmacokinetics analysis for both cohorts. A total of 48 patients in the status cohort and 15 patients in the elective cohort were enrolled. Median age was 7 years, 2 months. The population pharmacokinetics parameters were: clearance, 1.2 mL/min/kg; half-life, 16.8 hours; and volume of distribution, 1.5 L/kg. On the basis of the pharmacokinetics model, a 0.1 mg/kg dose is expected to achieve concentrations of approximately 100 ng/mL and maintain concentrations >30 to 50 ng/mL for 6 to 12 hours. A second dose of 0.05 mg/kg would achieve desired therapeutic serum levels for approximately 12 hours without excessive sedation. Age-dependent dosing is not necessary beyond using a maximum initial dose of 4 mg. Lorazepam pharmacokinetics in convulsive SE is similar to earlier pharmacokinetics measured in pediatric patients with cancer, except for longer half-life, and similar to adult pharmacokinetics parameters except for increased clearance.
  The Journal of pediatrics 11/2011; 160(4):667-672.e2. · 4.02 Impact Factor
• Article: Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children.

  Brookie M Best, Edmund V Capparelli, Huy Diep, Steven S Rossi, Michael J Farrell, Elaine Williams, Grace Lee, John N van den Anker, Natella Rakhmanina
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  ABSTRACT: Lopinavir/ritonavir (Kaletra) is first-line therapy for pediatric HIV infection. In clinical practice, Kaletra tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children. This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had 2 separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets. PK blood samples were drawn at 0 (predose), 1, 2, 4, 6, 8, and 12 hours postdose. Lopinavir and ritonavir plasma concentrations measured by high-performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance. Wilcoxon signed-rank tests compared PK values between crushed and whole tablets. Twelve children, median age of 13 years (10-16 years), took 550/138 mg·m(-2) per day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC after crushed and whole tablets were 92 mg·hr·L(-1) and 144 mg·hr·L(-1), respectively, with an AUC ratio of 0.55 (P = 0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg·hr·L(-1) and 13.3 mg·hr·L(-1), respectively, with an AUC ratio of 0.53 (P = 0.006). Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2011; 58(4):385-91. · 4.43 Impact Factor
• Article: CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children.

  Natella Y Rakhmanina, Michael N Neely, Ron H N Van Schaik, Heather A Gordish-Dressman, Keetra D Williams, Steven J Soldin, John N van den Anker
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  ABSTRACT: CYP3A5, MDR1 (ABCB1), and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children. We conducted a prospective cohort study in children (4-18 years old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1, and SLCO1B1 genotypes were determined using polymerase chain reaction amplification with allelic discrimination assays. The 12-hour plasma area under the concentration-time curves (AUC) and clearances (CL) of LPV and RTV were estimated using noncompartmental models. HIV RNA viral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL, and HIV RNA. Fifty children (median age 11.2 years) were enrolled. Allele frequencies of the genotypes studied were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1, or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (P = 0.042) and a nearly significant association with decreased LPV CL (P = 0.063). None of the studied polymorphisms, including SLCO1B1 T521C, were associated with virologic outcome during 52 weeks of study follow-up. There was no statistically significant influence of the CYP3A5, ABCB1, or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with an increase in LPV AUC but was not associated with undetectable HIV RNA during the study period.
  Therapeutic drug monitoring 08/2011; 33(4):417-24. · 2.43 Impact Factor
• Article: CYP3A5, ABCB1, and SLCO1B1 Polymorphisms and Pharmacokinetics and Virologic Outcome of Lopinavir/Ritonavir in HIV-Infected Children

  Natella Y Rakhmanina, Michael N Neely, Ron HN Van Schaik, Heather A Gordish-Dressman, Keetra D Williams, Steven J Soldin, John N van den Anker
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  ABSTRACT: Objective: CYP3A5, MDR1 (ABCB1), and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children. Design and Methods: We conducted a prospective cohort study in children (4-18 years old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1, and SLCO1B1 genotypes were determined using polymerase chain reaction amplification with allelic discrimination assays. The 12-hour plasma area under the concentration-time curves (AUC) and clearances (CL) of LPV and RTV were estimated using noncompartmental models. HIV RNA viral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL, and HIV RNA. Results: Fifty children (median age 11.2 years) were enrolled. Allele frequencies of the genotypes studied were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1, or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (P = 0.042) and a nearly significant association with decreased LPV CL (P = 0.063). None of the studied polymorphisms, including SLCO1B1 T521C, were associated with virologic outcome during 52 weeks of study follow-up. Conclusions: There was no statistically significant influence of the CYP3A5, ABCB1, or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with an increase in LPV AUC but was not associated with undetectable HIV RNA during the study period.
  Therapeutic Drug Monitoring 07/2011; 33(4):417-424. · 2.49 Impact Factor
• Chapter: Drug–Herb Interactions in Patients with HIV/AIDS

  Natella Y. Rakhmanina, John N. van den Anker
  10/2010: pages 291 - 303; , ISBN: 9780470910108
• Source

  Available from: Nicholas Michael Mordwinkin

  Article: Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents?

  Natella Y Rakhmanina, John N van den Anker, Steven J Soldin, Ron H van Schaik, Nick Mordwinkin, Michael N Neely
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  ABSTRACT: Currently, therapeutic drug monitoring (TDM) of antiretroviral therapy (ART) is not performed in the United States as part of routine clinical care of an HIV-infected adolescent patient. TDM is recommended to rule out subtherapeutic drug concentrations and to differentiate among malabsorption, drug interactions, poor adherence, or increased drug metabolism or clearance as possible causes of decreased drug exposure. The use of TDM is also considered to assist in finding the optimal dose of a drug in patients whose virus has shown reduced susceptibility to that drug. The dosing of antiretroviral (ARV) drugs in adolescent patients with HIV infection depends on the chronologic age, weight, height, and the stage of sexual maturation. As a result of the limited data on the pharmacokinetics of ART during puberty, the transition of a dosing regimen from higher pediatric (weight and surface-based) to adult (fixed) range is not well defined. Developmental pharmacokinetic differences contribute to high variability in pediatric and adolescent patients and an increased frequency of suboptimal ARV exposure as compared to in adults. Individualized, concentration-targeted optimal dosing of ARV medications can be beneficial to patients for whom only limited dosing guidelines are available. This article describes three cases of the application of TDM in treatment-experienced adolescent patients whose ART was optimized using ARV TDM. TDM of ARV drugs is useful in managing the pharmacotherapy of HIV in adolescent patients and is well received by the adolescent patients with HIV and their families. Among others, the benefits of TDM provide evidence for adherence interventions and create grounds for enhanced education of the adolescent patient and involved adult caregivers about ART. Finally, TDM in adolescents provides valuable information about the clinical pharmacology of ART during puberty.
  Therapeutic drug monitoring 06/2010; 32(3):273-81. · 2.43 Impact Factor
• Article: Efavirenz in the therapy of HIV infection.

  Natella Y Rakhmanina, John N van den Anker
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  ABSTRACT: The use of the first generation non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) as a component of first-line antiretroviral therapy has been accepted worldwide. EFV is the only antiretroviral agent currently on the market that has been combined with emtricitabine and tenofovir disoproxil fumarate in a single tablet and administered once daily. This article reviews efficacy and safety data on EFV and the role of pharmacogenetics in EFV exposure. Published articles and conference presentations on EFV are reviewed. CYP2B6 genetic polymorphisms influence the metabolism of EFV. The CYP2B6 G to T polymorphism at position 516 is shown to be associated with elevated plasma concentrations and an increase in neurotoxicity of EFV, while the wild-type genotype has been associated with sub-therapeutic concentrations of EFV, potentially leading to the development of viral resistance. This polymorphism is significantly higher in sub-Saharan Africans and African Americans as compared to Hispanic, European and Asian populations. The significance of CYP2B6 polymorphism in EFV exposure indicates the need for prospective clinical studies to evaluate the utility of genotype-driven dose adjustments in populations of diverse descent.
  Expert Opinion on Drug Metabolism &amp Toxicology 01/2010; 6(1):95-103. · 3.12 Impact Factor
• Article: Treating an HIV-infected paediatric patient: an easy task?

  Natella Y Rakhmanina, John N van den Anker
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  ABSTRACT: HIV-infected children represent an incredibly diverse group of patients, ranging from neonates to young adults. With the change in age and maturity, paediatric highly active antiretroviral therapy (HAART) evolves from the meticulous twice-daily dosing of ml of liquid preparations to a choice of once-daily dosing of a single fixed-dose coformulated tablet. The use of simplified paediatric regimens could enhance the ability to achieve successful implementation of HAART in HIV-infected children. Pharmacokinetics and pharmacodynamic studies of antiretroviral drugs and their combinations need to be conducted in infants, children and adolescents to develop appropriate dosing in each of these specific groups.
  Antiviral therapy 01/2010; 15(3):293-6. · 3.16 Impact Factor
• Article: Nevirapine concentration in nonstimulated saliva: an alternative to plasma sampling in children with human immunodeficiency virus infection.

  Natella Y Rakhmanina, Edmund V Capparelli, John N van den Anker, Keetra Williams, John L Sever, Hans M L Spiegel, Steven J Soldin
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  ABSTRACT: The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since the introduction of NVP as part of the preferred first-line antiretroviral regimen for human immunodeficiency virus (HIV)-infected children in resource-limited settings. Adequate trough concentrations of NVP predict successful therapy, whereas subtherapeutic levels are correlated with virologic failure and development of resistance. The aim of this study was to determine the extent of agreement between total and free plasma NVP concentrations and nonstimulated saliva NVP concentrations and to evaluate the feasibility of saliva sampling as an alternative tool for therapeutic drug monitoring of NVP in children. The study was designed as an observational cohort analysis. NVP concentrations were obtained in paired plasma and saliva samples of pediatric patients receiving antiretroviral therapy, including NVP. NVP plasma and saliva concentrations were determined by a tandem-mass spectrometric method. The intraclass correlation coefficient and Bland-Altman analysis were used to evaluate agreement and to assess pattern in any discrepancies between measurements. For the random paired plasma and saliva NVP sampling, 19 African-American children (8 boys, 11 girls) with a median age of 8.0 years were enrolled. Two male subjects were recruited for the 12 hour NVP plasma and saliva pharmacokinetics study. The intraclass correlations between saliva and serum measurements of NVP concentrations indicated >90% agreement between these two modes of measurement. The saliva concentrations reflected the free concentrations very closely but were on average 34% higher. The Bland-Altman plots indicated that the discrepancy between saliva and plasma measures is consistent across the range of average NVP concentrations. Our study results strongly indicate agreement between saliva and plasma NVP concentrations in pediatric patients with HIV infection, on the basis of Bland-Altman analysis. Nonstimulated NVP saliva concentrations can be used as an alternative noninvasive, reliable, cost-effective method for direct measurement of adherence and application of therapeutic drug monitoring in NVP therapy.
  Therapeutic Drug Monitoring 03/2007; 29(1):110-7. · 2.49 Impact Factor
• Article: Pharmacological research in pediatrics: From neonates to adolescents.

  Natella Y Rakhmanina, John N van den Anker
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  ABSTRACT: The data guiding the dosing, efficacy and safety of medicines for children have lagged substantially as compared to the information available for adults. As a consequence, pediatricians faced with the prospect of confining their practice to medicines with adequate information have frequently resorted to prescribing medicines for unapproved uses (different dose, frequency, age group, route, indication or formulation). Although a long time in coming, the past decade, have witnessed a new era in drug development for children--an era that is still in its infancy, but which is currently showing signs of maturation. This review will give some of the history and current progress in pharmacological research and pediatric drug development.
  Advanced Drug Delivery Reviews 05/2006; 58(1):4-14. · 11.50 Impact Factor
• Article: Safety and pharmacokinetics of antiretroviral therapy during pregnancy.

  Natella Y Rakhmanina, John N van den Anker, Steven J Soldin
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  ABSTRACT: Combined antiretroviral therapy can reduce the transmission of human immunodeficiency virus (HIV) to an unborn child to less than two percent. An HIV-infected woman of childbearing age and her medical provider are in the unique position of making treatment decisions that not only will impact the woman's health but also that of her child. Treatment recommendations for pregnant women infected with HIV state that therapies of known benefit to women should not be withheld during pregnancy, unless there are known adverse effects for the mother and fetus, and these adverse effects outweigh the benefit for the women. However, the recommendations of antiretroviral drugs for the treatment of HIV-infected pregnant women are subject to unique considerations, including potential changes in dosing requirement resulting from physiologic changes associated with pregnancy, and potential adverse effects on the development of the fetus and/or newborn. Currently there is a general lack of pharmacokinetic data in pregnant HIV-infected women. The limited available information suggests that pregnant women may be exposed to subtherapeutic drug levels of certain antiretroviral agents during the later stages of pregnancy, which can lead to the failure of virologic suppression, development of resistance and increased risk of vertical transmission of HIV infection. The available pharmacokinetic data regarding the use of antiretroviral therapy in pregnancy is reviewed.
  Therapeutic Drug Monitoring 05/2004; 26(2):110-5. · 2.49 Impact Factor
• Article: Therapeutic drug monitoring of antiretroviral therapy.

  Natella Y Rakhmanina, John N van den Anker, Steven J Soldin
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  ABSTRACT: The concept of managing pharmacotherapy based on plasma drug concentrations has been used for decades in a variety of clinical settings. The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. A primary characteristic of TDM of antiretroviral drugs is that multiple agents are concomitantly used in HAART regimens. Inadequate drug concentrations may lead to evolution of drug resistance mutations and endanger present and future treatment options. A number of clinical trials have demonstrated that drug serum concentrations are an important factor in response to therapy for HIV, but whether TDM will become a tool for the routine management of HIV infection remains to be determined. This review includes an illustrative case report of measuring concentrations of antiretroviral drugs in a pediatric patient.
  AIDS PATIENT CARE and STDs 02/2004; 18(1):7-14. · 2.41 Impact Factor
• Article: Introduction: psychopharmacology.

  Adelaide S Robb, John N van den Anker
  Developmental Disabilities Research Reviews 16(3):231-2. · 4.04 Impact Factor