SUNY at Stony Brook, Stony Brook, NY, USA (Prof S Nachman MD); Levine Children’s Hospital at Caro... more SUNY at Stony Brook, Stony Brook, NY, USA (Prof S Nachman MD); Levine Children’s Hospital at Carolinas Medical Center, Charlotte, NC, USA (A Ahmed MD); Indus Hospital, Pakistan (F Amanullah MBBS); Harvard Medical School, Boston, MA, USA (M C Becerra ScD); European Medicines Agency, London, UK (R Botgros MD, M Powell MD); Médecins Sans Frontières, Access Campaign, Geneva, Switzerland (G Brigden MBchB); National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, MD, USA (R Browning MSN, R Hafner MD, M Makhene MD); TB Alliance, New York, NY, USA (E Gardiner MSc, C Mendel MD, S Murray MD); Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa (Prof A Hesseling MD, Prof H S Schaaf MBCHb); Department of Pharmacology and Toxicology, University of the Philippines, Manila, Philippines (C How MD); Henry M Jackson Foundation—Division of AIDS, Contractor to National Institutes of...
Journal of the Pediatric Infectious Diseases Society
Pharmacological interactions limit treatment options for children living with human immunodeficie... more Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to <2 years receiving concurrent rifampin to treat TB. Clinical Trials Registration NCT01751568.
To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavi... more To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 μg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 μg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.
Children younger than 18 years account for a substantial proportion of patients with tuberculosis... more Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally eff ective, are hampered by high pill burden, long duration of treatment, coexistent toxic eff ects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.
HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric H... more HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. Methods: Antiretroviral-naïve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA > 5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa. Results: Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA ≤ 400 cpm. At week 48, 69.5% of naïve and 43.3% of experienced subjects had HIV RNA ≤ 400 cpm; median CD4 increase was 196.5 cells/mm 3. The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels ≥ 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC > 199 mg/dL increasing from 1% at baseline to 5.7%. Conclusions: Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels.
The use of therapeutic proteins, such as Ig-based fusion proteins, is assuming an important place... more The use of therapeutic proteins, such as Ig-based fusion proteins, is assuming an important place in medicine. 1,2 Because of the IgG Fc region of these proteins, there is a possibility that interactions with Fc receptors may interfere with dose-dependent therapeutics. 3 PRO 542 (CD4-IgG 2) is a tetravalent fusion protein designed to prevent the attachment of the virus through its glycoprotein 120 to the CD4 molecule on monocytes/macrophages and T cells. 4, 5 Our first study of PRO 542 in HIV-1-infected children documented that it was a safe therapeutic; exhibited linear dose-concentration pharmacokinetic behavior in 0.2, 1.0, 5.0, and 10.0 mg/kg studies; and possessed antiviral properties as assessed by plasma HIV-1-RNA
The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would pr... more The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent motherto-child transmission in HIV-infected pregnant women. Methods ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery. Results In cohort 1 (n 5 6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n 5 4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption. Conclusions While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.
IFN-Y secreting memory T-cells can be used as potential biomarkers to evaluate immunogenicity of ... more IFN-Y secreting memory T-cells can be used as potential biomarkers to evaluate immunogenicity of Keyhole Limpet Hemocyanin (KLH). Method: Eight healthy volunteers were immunized with KLH at d1 (pre-immunization) and d29, blood was then obtained for a Peripheral blood mononuclear cells (PBMC) harvest at d1, d29, d36 and d43. Cells from the different time points were frozen at À808C overnight and stored in liquid nitrogen. The PBMC's were challenged with KLH antigen in vitro and the IFN-Y secreting T-cells were assessed by an ELISPOT assay. Results: A significant increase (5.6-7.5 fold) in IFN-Y spot forming T-cells (SFCs) was evident when cells from day 29 time point (before booster) were compared to later time points at day 36 and day 43, suggesting the elicitation of a KLH mediated CD4 restricted T-cell response. Conclusions: KLH immunization in healthy volunteers elicited a significant T-cell mediated response that could be assessed by monitoring the cytokine profile of KLH specific IFN-Y secreting memory T-cells from PBMCs.
The Pediatric Infectious Disease Journal, Feb 1, 2015
HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric H... more HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. Methods: Antiretroviral-naïve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA > 5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa. Results: Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA ≤ 400 cpm. At week 48, 69.5% of naïve and 43.3% of experienced subjects had HIV RNA ≤ 400 cpm; median CD4 increase was 196.5 cells/mm 3. The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels ≥ 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC > 199 mg/dL increasing from 1% at baseline to 5.7%. Conclusions: Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels.
Objective-To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV/r in chi... more Objective-To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV/r in children ages 91 days to 21 years.
SUNY at Stony Brook, Stony Brook, NY, USA (Prof S Nachman MD); Levine Children’s Hospital at Caro... more SUNY at Stony Brook, Stony Brook, NY, USA (Prof S Nachman MD); Levine Children’s Hospital at Carolinas Medical Center, Charlotte, NC, USA (A Ahmed MD); Indus Hospital, Pakistan (F Amanullah MBBS); Harvard Medical School, Boston, MA, USA (M C Becerra ScD); European Medicines Agency, London, UK (R Botgros MD, M Powell MD); Médecins Sans Frontières, Access Campaign, Geneva, Switzerland (G Brigden MBchB); National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, MD, USA (R Browning MSN, R Hafner MD, M Makhene MD); TB Alliance, New York, NY, USA (E Gardiner MSc, C Mendel MD, S Murray MD); Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa (Prof A Hesseling MD, Prof H S Schaaf MBCHb); Department of Pharmacology and Toxicology, University of the Philippines, Manila, Philippines (C How MD); Henry M Jackson Foundation—Division of AIDS, Contractor to National Institutes of...
Journal of the Pediatric Infectious Diseases Society
Pharmacological interactions limit treatment options for children living with human immunodeficie... more Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to <2 years receiving concurrent rifampin to treat TB. Clinical Trials Registration NCT01751568.
To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavi... more To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 μg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 μg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.
Children younger than 18 years account for a substantial proportion of patients with tuberculosis... more Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally eff ective, are hampered by high pill burden, long duration of treatment, coexistent toxic eff ects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.
HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric H... more HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. Methods: Antiretroviral-naïve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA > 5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa. Results: Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA ≤ 400 cpm. At week 48, 69.5% of naïve and 43.3% of experienced subjects had HIV RNA ≤ 400 cpm; median CD4 increase was 196.5 cells/mm 3. The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels ≥ 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC > 199 mg/dL increasing from 1% at baseline to 5.7%. Conclusions: Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels.
The use of therapeutic proteins, such as Ig-based fusion proteins, is assuming an important place... more The use of therapeutic proteins, such as Ig-based fusion proteins, is assuming an important place in medicine. 1,2 Because of the IgG Fc region of these proteins, there is a possibility that interactions with Fc receptors may interfere with dose-dependent therapeutics. 3 PRO 542 (CD4-IgG 2) is a tetravalent fusion protein designed to prevent the attachment of the virus through its glycoprotein 120 to the CD4 molecule on monocytes/macrophages and T cells. 4, 5 Our first study of PRO 542 in HIV-1-infected children documented that it was a safe therapeutic; exhibited linear dose-concentration pharmacokinetic behavior in 0.2, 1.0, 5.0, and 10.0 mg/kg studies; and possessed antiviral properties as assessed by plasma HIV-1-RNA
The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would pr... more The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent motherto-child transmission in HIV-infected pregnant women. Methods ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery. Results In cohort 1 (n 5 6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n 5 4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption. Conclusions While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.
IFN-Y secreting memory T-cells can be used as potential biomarkers to evaluate immunogenicity of ... more IFN-Y secreting memory T-cells can be used as potential biomarkers to evaluate immunogenicity of Keyhole Limpet Hemocyanin (KLH). Method: Eight healthy volunteers were immunized with KLH at d1 (pre-immunization) and d29, blood was then obtained for a Peripheral blood mononuclear cells (PBMC) harvest at d1, d29, d36 and d43. Cells from the different time points were frozen at À808C overnight and stored in liquid nitrogen. The PBMC's were challenged with KLH antigen in vitro and the IFN-Y secreting T-cells were assessed by an ELISPOT assay. Results: A significant increase (5.6-7.5 fold) in IFN-Y spot forming T-cells (SFCs) was evident when cells from day 29 time point (before booster) were compared to later time points at day 36 and day 43, suggesting the elicitation of a KLH mediated CD4 restricted T-cell response. Conclusions: KLH immunization in healthy volunteers elicited a significant T-cell mediated response that could be assessed by monitoring the cytokine profile of KLH specific IFN-Y secreting memory T-cells from PBMCs.
The Pediatric Infectious Disease Journal, Feb 1, 2015
HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric H... more HIV RepoRts Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. Methods: Antiretroviral-naïve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA > 5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa. Results: Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA ≤ 400 cpm. At week 48, 69.5% of naïve and 43.3% of experienced subjects had HIV RNA ≤ 400 cpm; median CD4 increase was 196.5 cells/mm 3. The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels ≥ 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC > 199 mg/dL increasing from 1% at baseline to 5.7%. Conclusions: Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels.
Objective-To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV/r in chi... more Objective-To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV/r in children ages 91 days to 21 years.
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Papers by Pearl Samson