Niklas Lindegardh

University of Oxford, Oxford, England, United Kingdom

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Publications (130)607.93 Total impact

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    ABSTRACT: One promising new Artemisinin-based combination therapies (ACTs) is dihydroartemisinin-piperaquine (DHA-PQ). However, the pharmacokinetics of piperaquine and the relationship between drug levels and clinical efficacy are incompletely characterized, particularly in children.
    PLoS ONE 08/2014; 9(8):e103200. · 3.53 Impact Factor
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    ABSTRACT: Objectives: Mefloquine/artesunate has recently been developed as a fixed-dose combination, providing a promising rescue/alternative treatment for malaria during pregnancy. However, limited data are available on the effect of pregnancy on its pharmacokinetic properties. This study was conducted to assess the pharmacokinetic properties of mefloquine/carboxymefloquine and artesunate/dihydroartemisinin in pregnant and non-pregnant women with uncomplicated malaria. Methods: Twenty-four women in their second and third trimesters of pregnancy and 24 paired non-pregnant women were enrolled. All patients were treated for uncomplicated Plasmodium falciparum malaria with a standard fixed-dose combination of oral mefloquine and artesunate one daily over 3 days. Frequent blood samples were collected before treatment and at scheduled times post-dose for the drug measurements and pharmacokinetic analyses. The study was registered at (identifier: NCT00701961). Results: The total median exposure to mefloquine and dihydroartemisinin was not significantly different between the pregnant and non-pregnant women (P.0.05). Therewas a trend of higher exposure tomefloquine in the pregnant women, but this difference did not reach statistical significance (656700 versus 542400 h×ng/mL; P¼0.059). However, the total exposure to carboxymefloquine was 49% lower during pregnancy (735600 versus 1499000 h×ng/mL; P,0.001) and the total drug exposure to artesunate was 42% higher during pregnancy (89.0 versus 62.9 h×ng/mL; P¼0.039) compared with non-pregnant controls. Conclusions: The plasma levels of mefloquine and dihydroartemisinin appeared to be similar in both pregnant and non-pregnant women, but there were significant differences in carboxymefloquine and artesunate exposure. The data presented here do not warrant a dose adjustment in pregnant patients, but an extensive analysis of the data could provide a better understanding of these findings.
    Journal of Antimicrobial Chemotherapy 06/2014; 2014 Jun 2.. · 5.34 Impact Factor
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    ABSTRACT: Comprehensive assessment of antimalarial drug resistance should include measurements of antimalarial blood or plasma concentrations in clinical trials and in individual assessments of treatment failure, so that true resistance can be differentiated from inadequate drug exposure. Pharmacometric modelling is necessary to assess pharmacokinetic-pharmacodynamic relationships in different populations to optimize dosing. To accomplish both effectively, and to allow comparison of data from different laboratories, it is essential that drug concentration measurement is accurate. Proficiency testing (PT) of laboratory procedures are necessary for verification of assay results. Within WWARN, the goal of the quality assurance/quality control (QA/QC) programme is to facilitate and sustain high-quality antimalarial assays. The QA/QC programme consists of an international PT programme for pharmacology laboratories and a reference material (RM) programme for the provision of antimalarial drug standards, metabolites and internal standards for laboratory use. The RM programme currently distributes accurately weighed quantities of antimalarial drug standards, metabolites and internal standards to 44 pharmacology, in vitro and drug quality laboratories. The pharmacology PT programme has sent samples to 8 laboratories in 4 rounds of testing. WWARN technical experts have provided advice for correcting identified problems to improve performance of subsequent analysis, and ultimately improved the quality of data. Many participants have demonstrated substantial improvements over subsequent rounds of PT. The WWARN QA/QC programme has improved the quality and value of antimalarial drug measurement in laboratories globally. It is a model that has potential to be applied to strengthening laboratories more widely and improving the therapeutics of other infectious diseases.
    Antimicrobial Agents and Chemotherapy 04/2014; · 4.57 Impact Factor
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    ABSTRACT: Artemether (AM) plus azithromycin (AZ) rectal co-formulations were studied to provide pre-referral treatment for children with severe febrile illnesses in malaria-endemic areas. The target profile required that such product should be cheap, easy to administer by non-medically qualified persons, rapidly effective against both malaria and bacterial infections. Analytical and pharmacotechnical development, followed by in vitro and in vivo evaluation, were conducted for various AMAZ coformulations. Of the formulations tested, stability was highest for dry solid forms and bioavailability for hard gelatin capsules; AM release from AMAZ rectodispersible tablet was suboptimal due to a modification of its micro-crystalline structure.
    International Journal of Pharmaceutics 04/2014; · 3.99 Impact Factor
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    ABSTRACT: Oseltamivir is the most widely used anti-influenza drug. In the 2009 H1N1 pandemic, in which the influenza viruses were oseltamivir sensitive, obesity was identified as a risk factor for severe disease and unfavorable outcomes. The aim of this study was to investigate the pharmacokinetic properties of oseltamivir and its active metabolite, oseltamivir carboxylate, in obese and nonobese healthy subjects. A single-dose, randomized, two-sequence crossover study was conducted in 12 obese and 12 nonobese healthy Thai volunteers. Each volunteer was given 75 mg and 150 mg oseltamivir orally with an intervening washout period of more than 3 days. The pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated using a noncompartmental approach. The median (range) body mass indexes (BMIs) for obese subjects were 33.8 kg/m2 (30.8 to 43.2) and 22.2 (18.8 to 24.2) for nonobese subjects. The pharmacokinetic parameters of oseltamivir carboxylate, the active metabolite of oseltamivir, were not significantly different between obese and nonobese subjects for both 75-mg and 150-mg doses. Both doses were well tolerated. Despite the lower dose per kilogram body weight in obese subjects, there was no significant difference in the exposure of oseltamivir carboxylate between the obese and nonobese groups. Standard dosing is appropriate for obese subjects. (The study was registered at under registration no. NCT 01049763.) FOOTNOTES Received 3 September 2013. Returned for modification 20 November 2013. Accepted 17 December 2013. Address correspondence to Podjanee Jittamala, podjanee{at} Published ahead of print 23 December 2013 Copyright © 2014 Jittamala et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license.
    Antimicrobial Agents and Chemotherapy 03/2014; 58(3). · 4.45 Impact Factor
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    ABSTRACT: Previously published literature reports a varying impact of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for three days with (n=15) and without (n=15) concomitant food to patients with uncomplicated P. falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte-Carlo mapped power approach was applied to evaluate the relationship between statistical power and a varying degree of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during the recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte-Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.
    Antimicrobial Agents and Chemotherapy 01/2014; · 4.57 Impact Factor
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    ABSTRACT: Artesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ). This was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods. Exposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC0-24 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC0-96 14 571 versus 21 648 ng·h/mL, P < 0.01). The AUCDEAQ/AUCamodiaquine ratio was not different between groups (ART group 116 versus control group 102, P = 0.67). Subjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.
    Journal of Antimicrobial Chemotherapy 01/2014; · 5.34 Impact Factor
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    ABSTRACT: Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected Rhesus macaques similarly to HIV-infected humans. In contrast, SIV infection of natural hosts is characterized by a down regulation of innate acute responses to the virus within few weeks from the infection and results in limited pathology. Chloroquine (CQ) has been used in the treatment or prevention of malaria and has recently been shown to cause a decrease of immune-activation and CD4-cell loss in HIV infected individuals treated with antiretroviral therapy. Here, we treated Rhesus macaques with CQ during the acute phase of SIVmac251 infection with intent to decrease viral-induced immune activation, and possibly limit disease progression. Contrary to what is expected, CQ treatment resulted in a temporary increased expression of IFN-stimulating genes and it worsened the recovery of CD4+ T cells in the blood. Our findings confirm recent results observed in asymptomatic HIV infection patients, and suggest that CQ does not provide an obvious benefit in the absence of antiretroviral therapy.
    AIDS research and human retroviruses 11/2013; · 2.18 Impact Factor
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    ABSTRACT: Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether-lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e83; doi:10.1038/psp.2013.59; advance online publication 13 November 2013.
    CPT: pharmacometrics & systems pharmacology. 11/2013; 2:e83.
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    ABSTRACT: Acidosis is an important cause of mortality in severe falciparum malaria. Lactic acid is a major contributor to metabolic acidosis, but accounts for only one-quarter of the strong anion gap. Other unidentified organic acids have an independent strong prognostic significance for a fatal outcome. In this study, a simultaneous bio-analytical method for qualitative and quantitative assessment in plasma and urine of eight small organic acids potentially contributing to acidosis in severe malaria was developed and validated. High-throughput strong anion exchange solid-phase extraction in a 96-well plate format was used for sample preparation. Hydrophilic interaction liquid chromatography (HILIC) coupled to negative mass spectroscopy was utilized for separation and detection. Eight possible small organic acids; l-lactic acid (LA), α-hydroxybutyric acid (aHBA), β-hydroxybutyric acid (bHBA), p-hydroxyphenyllactic acid (pHPLA), malonic acid (MA), methylmalonic acid (MMA), ethylmalonic acid (EMA) and α-ketoglutaric acid (aKGA) were analyzed simultaneously using a ZIC-HILIC column with an isocratic elution containing acetonitrile and ammonium acetate buffer. This method was validated according to U.S. Food and Drug Administration guidelines with additional validation procedures for endogenous substances. Accuracy for all eight acids ranged from 93.1% to 104.0%, and the within-day and between-day precisions (i.e. relative standard deviations) were lower than 5.5% at all tested concentrations. The calibration ranges were: 2.5-2500μg/mL for LA, 0.125-125μg/mL for aHBA, 7.5-375μg/mL for bHBA, 0.1-100μg/mL for pHPLA, 1-1000μg/mL for MA, 0.25-250μg/mL for MMA, 0.25-100μg/mL for EMA, and 30-1500μg/mL for aKGA. Clinical applicability was demonstrated by analyzing plasma and urine samples from five patients with severe falciparum malaria; five acids had increased concentrations in plasma (range LA=177-1169μg/mL, aHBA=4.70-38.4μg/mL, bHBA=7.70-38.0μg/mL, pHPLA=0.900-4.30μg/mL and aKGA=30.2-32.0) and seven in urine samples (range LA=11.2-513μg/mL, aHBA=1.50-69.5μg/mL, bHBA=8.10-111μg/mL, pHPLA=4.30-27.7μg/mL, MMA=0.300-13.3μg/mL, EMA=0.300-48.1μg/mL and aKGA=30.4-107μg/mL). In conclusion, a novel bioanalytical method was developed and validated which allows for simultaneous quantification of eight small organic acids in plasma and urine. This new method may be a useful tool for the assessment of acidosis in patients with severe malaria, and other conditions complicated by acidosis.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 10/2013; 941C:116-122. · 2.78 Impact Factor
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    ABSTRACT: Abstract OBJECTIVE: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. DESIGN: Double blind randomised trial. SETTING: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. PARTICIPANTS: Patients aged ≥ 1 year admitted to hospital with confirmed severe influenza. INTERVENTIONS: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). MAIN OUTCOME MEASURE: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. RESULTS: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found. CONCLUSIONS: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. REGISTRATION: Clinical Trials NCT00298233.
    BMJ. 05/2013; 346(f3039):1-16.
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    ABSTRACT: Oseltamivir and oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous blood to plasma ratios were 1.42 (0.920-1.97) for oseltamivir and 0.673 (0.564-0.814) for oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737-3.16) for oseltamivir and 0.685 (0.502-1.34) for oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood.
    Antimicrobial Agents and Chemotherapy 03/2013; · 4.57 Impact Factor
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    ABSTRACT: Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries. A non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar. Parasite density was measured every 12 hours until two consecutive negative smears were obtained. Participants were followed weekly at the study clinic for three additional weeks. Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment. Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels. The median (range) parasite clearance half-life and time were 4.8 (2.1-9.7) and 60 (24-96) hours, respectively. The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections. Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment. Parasite clearance was not associated with drug pharmacokinetics. A subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia. Resistance containment efforts are underway in Myanmar. Australian New Zealand Clinical Trials Registry ACTRN12610000896077.
    PLoS ONE 03/2013; 8(3):e57689. · 3.53 Impact Factor
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    ABSTRACT: Background. The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short half-life drug artesunate improves parasite clearance in falciparum malaria in the two regions.Methods. In Pailin, Western Cambodia (from 2008 to 2010) and Wang Pha, North-western Thailand (2009-2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/day as single or twice-daily dose for 7 days, or artesunate 8 mg/kg/day as single or twice daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence up to 63-days follow-up were assessed. Trial registration: ISRCTN15351875.Results. A total of 159 patients were enrolled. Overall median (IQR) parasitaemia half-life (half-life) was 6.03 (4.89-7.28) hours in Pailin versus 3.42 (2.20-4.85) hours in Wang Pha (p=0.0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 out of 79 patients in Pailin and 5/80 in Wang Pha and was not different between treatment arms (p=0.68). High dose artesunate was associated with transient reticulocytopenia and in one patient with transient neutropenia (0.78 x 10(3)/μL) at day 14.Conclusions. Increasing the artesunate treatment dose up to 8 mg/kg/day or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum.
    Clinical Infectious Diseases 03/2013; 56(5):e48-e58. · 9.42 Impact Factor
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    ABSTRACT: Background. Despite its primary use in children, pharmacokinetic/pharmacodynamic (PK/PD) data on dihydroartemisinin-piperaquine (DP) in young children is lacking.Methods. We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 treatments for malaria occurring over 5 months of follow-up. Malaria follow-up was conducted actively to day 28 and passively to day 63.Results. Median day-7 capillary piperaquine concentration was 41.9&emsp14;ng/mL. Low piperaquine concentrations were associated with the risk of recurrent malaria up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TS) prophylaxis. In children not taking TS, piperaquine concentrations were only modestly associated with the risk of recurrent malaria. However, for children on TS, associations were strong and evident for all sampling days. Day 7 concentrations ≤27.3&emsp14;ng/mL were highly predictive of the risk for recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria.Conclusions. These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlates with risk of recurrent malaria after DP treatment in children on TS prophylaxis. Interestingly, despite strong associations, infants remain at risk for malaria even in the presence of residual levels of piperaquine.
    The Journal of Infectious Diseases 02/2013; · 5.85 Impact Factor
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    ABSTRACT: Parenteral artesunate (ARS) is the drug of choice for the treatment of severe malaria. Pharmacokinetics data on intramuscular ARS are limited with respect to the main treatment group that carries the highest mortality, namely, critically ill children with severe malaria. A population pharmacokinetic study of ARS and dihydroartemisinin (DHA) was conducted from sparse sampling in 70 Tanzanian children of ages 6 months to 11 years. All the children had been admitted with severe falciparum malaria and were treated with intramuscular ARS (2.4 mg/kg at 0, 12, and 24 h). Venous plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling (NONMEM). A one-compartment disposition model accurately described first-dose population pharmacokinetics of ARS and DHA. Body weight significantly affected clearance and apparent volume of distribution (P < 0.001), resulting in lower ARS and DHA exposure levels in smaller children. An adapted dosing regimen including a practical dosing table per weight band is proposed for young children based on the pharmacokinetic model.Clinical Pharmacology & Therapeutics (2013); advance online publication 20 March 2013. doi:10.1038/clpt.2013.26.
    Clinical Pharmacology &#38 Therapeutics 02/2013; · 6.85 Impact Factor
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    ABSTRACT: Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t(1/2) β) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t(1/2) β of approximately 3.0 hours). Peramivir is slowly eliminated (t(1/2) β of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation.
    The Journal of Clinical Pharmacology 02/2013; 53(2):119-39. · 2.47 Impact Factor
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    ABSTRACT: BACKGROUND: Antiviral resistance among influenza A viruses is associated with high morbidity and mortality in immunocompromised hosts. However, treatment strategies for drug-resistant influenza A are not established. A triple combination antiviral drug (TCAD) regimen consisting of amantadine, oseltamivir, and ribavirin demonstrated good efficacy in an animal model. METHODS: We first analyzed pharmacokinetics of TCAD therapy in healthy volunteers. We then performed a pilot study of TCAD in patients undergoing chemotherapy or hematopoietic cell transplantation. Amantadine (75 mg), oseltamivir (50 mg), and ribavirin (200 mg) were administered three times a day for 10 days. The safety and pharmacokinetics of TCAD therapy were monitored. RESULTS: Pharmacokinetics (PK) of TCAD therapy in healthy volunteers was shown to be similar to the PK of each drug individually from a single dose. In the pilot study, six immunocompromised patients received TCAD therapy and one patient received oseltamivir monotherapy. All but one patient completed 10 days of TCAD therapy without side effects; one patient receiving TCAD was withdrawn from the study because of respiratory failure and ultimately recovered. Viral load was decreased after TCAD therapy despite the presence of either amantadine- or oseltamivir- resistant virus in two cases. One patient with 2009 influenza A/H1N1 receiving oseltamivir monotherapy developed confirmed oseltamivir-resistance during treatment. CONCLUSIONS: TCAD therapy had similar pharmacokinetics to each individual antiviral during monotherapy following a single dose and can be administered safely in immunocompromised patients.
    Antiviral therapy 12/2012; · 3.14 Impact Factor
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    ABSTRACT: Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of three month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought.
    International Journal of Pharmaceutics 12/2012; · 3.99 Impact Factor

Publication Stats

3k Citations
607.93 Total Impact Points


  • 2011–2014
    • University of Oxford
      • Centre for Tropical Medicine
      Oxford, England, United Kingdom
  • 2004–2014
    • Mahidol University
      • Faculty of Tropical Medicine
      Krung Thep, Bangkok, Thailand
  • 2010–2013
    • Mahidol Oxford Tropical Medicine Research Unit (MORU)
      Krung Thep, Bangkok, Thailand
    • Army Medical College
      Ralalpindi, Punjab, Pakistan
    • Universidade do Algarve
      Фару, Faro, Portugal
  • 2012
    • University of Khartoum
      Al Kharţūm, Khartoum State, Sudan
    • Karolinska Institutet
      • Department of Medicine, Solna
      Stockholm, Stockholm, Sweden
    • University of Ibadan
      • College of Medicine
      Ibadan, Oyo State, Nigeria
    • Makerere University
      • Infectious Diseases Institute
      Kampala, Central Region, Uganda
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2006–2011
    • Shoklo Malaria Research Unit
      Branch Amphoe Mē Sōhd, Tak, Thailand
  • 2000–2011
    • Dalarna University
      Fahlun, Dalarna, Sweden
  • 2009
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
  • 2007
    • National Institute of Health Research and Development
      Batavia, Jakarta Raya, Indonesia
    • University of Cape Town
      • Division of Clinical Pharmacology
      Cape Town, Province of the Western Cape, South Africa
  • 2006–2007
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 2002
    • Uppsala University
      • Division of Analytical Pharmaceutical Chemistry
      Uppsala, Uppsala, Sweden