| 1. |
- Abdalla, H., et al.
(författare)
-
Gamma-ray blazar spectra with HESS II mono analysis : The case of PKS2155-304 and PG1553+113
- 2017
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 600
-
Tidskriftsartikel (refereegranskat)abstract
- Context. The addition of a 28 m Cherenkov telescope (CT5) to the H.E.S.S. array extended the experiment's sensitivity to lower energies. The lowest energy threshold is obtained using monoscopic analysis of data taken with CT5, providing access to gamma-ray energies below 100 GeV for small zenith angle observations. Such an extension of the instrument's energy range is particularly beneficial for studies of active galactic nuclei with soft spectra, as expected for those at a redshift >= 0.5. The high-frequency peaked BL Lac objects PKS 2155-304 (z = 0.116) and PG 1553 + 113 (0.43 < z < 0.58) are among the brightest objects in the gamma-ray sky, both showing clear signatures of gamma-ray absorption at E > 100 GeV interpreted as being due to interactions with the extragalactic background light (EBL). Aims. The aims of this work are twofold: to demonstrate the monoscopic analysis of CT5 data with a low energy threshold, and to obtain accurate measurements of the spectral energy distributions (SED) of PKS 2155-304 and PG 1553 + 113 near their SED peaks at energies approximate to 100 GeV. Methods. Multiple observational campaigns of PKS 2155 304 and PG 1553 + 113 were conducted during 2013 and 2014 using the full H.E.S.S. II instrument (CT1-5). A monoscopic analysis of the data taken with the new CT5 telescope was developed along with an investigation into the systematic uncertainties on the spectral parameters which are derived from this analysis. Results. Using the data from CT5, the energy spectra of PKS 2155 304 and PG 1553 + 113 were reconstructed down to conservative threshold energies of 80 GeV for PKS 2155 304, which transits near zenith, and 110 GeV for the more northern PG 1553 + 113. The measured spectra, well fitted in both cases by a log-parabola spectral model ( with a 5.0 similar to statistical preference for non-zero curvature for PKS 2155 304 and 4.5 sigma for PG 1553+113), were found consistent with spectra derived from contemporaneous Fermi-LAT data, indicating a sharp break in the observed spectra of both sources at E approximate to 100 GeV. When corrected for EBL absorption, the intrinsic H.E.S.S. II mono and Fermi-LAT spectrum of PKS 2155 304 was found to show significant curvature. For PG 1553+113, however, no significant detection of curvature in the intrinsic spectrum could be found within statistical and systematic uncertainties.
|
|
| 2. |
- Choy, Steve, et al.
(författare)
-
Identification of the primary mechanism of action of an insulin secretagogue from meal test data in healthy volunteers based on an integrated glucose-insulin model
- 2013
-
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer. - 1567-567X .- 1573-8744. ; 40:1, s. 1-10
-
Tidskriftsartikel (refereegranskat)abstract
- The integrated glucose–insulin (IGI) model is a previously developed semi-mechanistic model that incorporates control mechanisms for the regulation of glucose production, insulin secretion, and glucose uptake. It has been shown to adequately describe insulin and glucose profiles in both type 2 diabetics and healthy volunteers following various glucose tolerance tests. The aim of this study was to investigate the ability of the IGI model to correctly identify the primary mechanism of action of glibenclamide (Gb), based on meal tolerance test (MTT) data in healthy volunteers. IGI models with different mechanism of drug action were applied to data from eight healthy volunteers participating in a randomized crossover study with five single-dose tests (placebo and four drug arms). The study participants were given 3.5 mg of Gb, intravenously or orally, or 3.5 mg of the two main metabolites M1 and M2 intravenously, 0.5 h prior to a standardized breakfast with energy content of 1800 kJ. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed using NONMEM®. Drug effects that increased insulin secretion resulted in the best model fit, thus identifying the primary mechanism of action of Gb and metabolites as insulin secretagogues. The model also quantified the combined effect of Gb, M1 and M2 to have a fourfold maximal increase on endogenous insulin secretion, with an EC50 of 169.1 ng mL−1 for Gb, 151.4 ng mL−1 for M1 and 267.1 ng mL−1 for M2. The semi-mechanistic IGI model was successfully applied to MTT data and identified the primary mechanism of action for Gb, quantifying its effects on glucose and insulin time profiles.
|
|
| 3. |
- Earp, Justin C., et al.
(författare)
-
Esomeprazole FDA Approval in Children With GERD : Exposure-Matching and Exposure-Response
- 2017
-
Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : LIPPINCOTT WILLIAMS & WILKINS. - 0277-2116 .- 1536-4801. ; 65:3, s. 272-277
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. Methods: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. Results: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching C-max values with adults. Conclusions: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposureresponse for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.
|
|
| 4. |
- Jönsson, Siv, et al.
(författare)
-
Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients
- 2011
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 55:9, s. 4230-4237
-
Tidskriftsartikel (refereegranskat)abstract
- Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.
|
|
| 5. |
- Kredo, T., et al.
(författare)
-
Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients
- 2011
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 55:12, s. 5616-5623
-
Tidskriftsartikel (refereegranskat)abstract
- Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naive patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naive groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC((0-8 h))] (P < 0.0001) and dihydroartemisinin AUC((60-68 h)) (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (T(max)). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.
|
|
| 6. |
- Ross, I. L., et al.
(författare)
-
Salivary Cortisol Day Curves in Addison's Disease in Patients on Hydrocortisone Replacement
- 2013
-
Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 45:1, s. 62-68
-
Tidskriftsartikel (refereegranskat)abstract
- Using salivary cortisol (SC) measurements, cortisol exposure in Addison's disease patients on hydrocortisone replacement was determined and compared with healthy controls. Cortisol pharmacokinetics was assessed in 31 patients with Addison's disease on replacement hydrocortisone doses ( median daily dose 20mg; range 5-50mg) and 30 healthy control subjects. Saliva samples (n=16) were collected between 08:00 and 00:00h in 1 day, using a passive drool technique. Cortisol exposure was evaluated by noncompartmental approach. In the patients, cortisol exposure was significantly higher than in controls: median inter-quartile range (IQR) peak cortisol (C-max ) 174.5 (59.3-837.0) vs. 6.50 (4.7-19.3) nmol/l, p=0.0001; area under the curve (AUC) 390.1 (177.1-928.9) vs. 21.4 (14.6-28.4) minutes*nmol/l, p=0.0001, trough cortisol level (C-min) 0.49 (0.49-0.96) vs. 0.49 (0.49-0.49) nmol/l, p=0.02, occurring at 480.0 (0.1- 660.0) vs. 405.0 (180.0-570.0) min, p=0.56. First peak cortisol was 174.5 (53.0-754.7) vs. 6.27 (3.90-8.47 ) nmol/l, p=0.0001 and second peak cortisol 18.90 (5.22-76.9) vs. 3.12 (1.76-4.79) nmol/l, p=0.0001. The time to first peak cortisol differed between the 2 groups, 30 (30-75) vs. 0.1 (0.1-30) minutes; p=0.0001. At doses studied, hydrocortisone replacement therapy results in cortisol pharmacokinetics being markedly different from endogenous cortisol profiles in healthy control subjects. Addison's disease patients had significantly higher SC levels compared to healthy control subjects.
|
|
| 7. |
- Svensson, Elin, et al.
(författare)
-
Integration of data from multiple sources for simultaneous modelling analysis : experience from nevirapine population pharmacokinetics
- 2012
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 74:3, s. 465-476
-
Tidskriftsartikel (refereegranskat)abstract
- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Integrating individual data from multiple sources in one simultaneous population analysis (sometimes called a mega-model) can address novel research questions and add power for covariate detection without requiring new clinical studies. However, the development of this type of model can be challenging and time consuming. Nevirapine is a non-nucleoside reverse transcriptase inhibitor commonly used for treatment of human immunodeficiency virus infection in resource-limited settings.WHAT THIS STUDY ADDS This study outlines a strategy for integration of data from multiple sources for modelling analysis. It provides suggestions on handling of missing covariates in the context of several data sources and a starting point for development of a multinational nevirapine mega-model. AIMS To propose a modelling strategy to efficiently integrate data from different sources in one simultaneous analysis, using nevirapine population pharmacokinetic data as an example.METHODS Data from three studies including 115 human immunodeficiency virus-infected South African adults were used. Patients were on antiretroviral therapy regimens including 200 mg nevirapine twice daily and sampled at steady state. A development process was suggested, implemented in NONMEM7 and the final model evaluated with an external data set.RESULTS A stepwise approach proved efficient. Model development started with the intensively sampled data. Data were added sequentially, using visual predictive checks for inspecting their compatibility with the existing model. Covariate exploration was carried out, and auxiliary regression models were designed for imputation of missing covariates. Nevirapine pharmacokinetics was described by a one-compartment model with absorption through two transit compartments. Body size was accounted for using allometric scaling. The model included a mixture of two subpopulations with different typical values of clearance, namely fast (3.12 l h-1) and slow metabolizers (1.45 l h-1), with 17% probability of belonging to the latter. Absorption displayed large between-occasion variability, and food slowed the absorption mean transit time from 0.6 to 2.5 h. Concomitant antitubercular treatment including rifampicin typically decreased bioavailability by 39%, with significant between-subject variability. Visual predictive checks of external validation data indicated good predictive performance.CONCLUSIONS The development strategy succeeded in integrating data from different sources to produce a model with robust parameter estimates. This work paves the way for the creation of a nevirapine mega-model, including additional data from numerous diverse sources.
|
|
| 8. |
- Wilmshurst, Jo M, et al.
(författare)
-
Rescue therapy with high-dose oral phenobarbitone loading for refractory status epilepticus
- 2010
-
Ingår i: Journal of Paediatrics and Child Health. - : Wiley. - 1034-4810 .- 1440-1754. ; 46:1-2, s. 17-22
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Parenteral phenobarbitone was unavailable in South Africa from 2005 to 2006. This study aimed to establish the effectiveness of enteral phenobarbitone in the management of childhood status epilepticus. Method: Patients in status epilepticus (December 2005-June 2006) received 20 mg/kg phenobarbitone via nasogastric tube in addition to standard status interventions (benzodiazepine boluses, phenytoin infusion). Phenobarbitone concentrations were taken post loading. Phenobarbitone population pharmacokinetics was analysed using non-linear mixed effects modelling. Results: Sixteen patients (7 female, 9 male) were assessed, median age 5 months (range 9 days-168 months). Nine patients received 20 mg/kg; the maximum total dosage administered was 80 mg/kg with a concentration of 283 micromol/L. The typical population value of the volume of distribution was 1.2 (95% confidence interval (CI): 0.8-1.6) L/kg with interindividual variability (as coefficient of variation) of 53% (95% CI, 9-74%). Seizure control was documented within 1 h (n= 8), 1(1)/(2) h (n= 1), 3 h (n= 1) and 4 h (n= 5) following enteral phenobarbitone loading. No adverse effects were apparent from the enteral phenobarbitone administration. Conclusion: Patients tolerated enteral loading with phenobarbitone. A single enteral loading dose resulted in adequate phenobarbitone exposure. This practice was a safe intervention for centres lacking parenteral phenobarbitone. Therapeutic concentrations and seizure control after enteral loading suggested a role for enteral phenobarbitone in the management of acute status epilepticus as well as prophylaxis against seizure recurrence.
|
|
| 9. |
- Zhang, Chao, et al.
(författare)
-
Population Pharmacokinetic Model for Adherence Evaluation Using Lamivudine Concentration Monitoring
- 2012
-
Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 34:4, s. 481-484
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Interpretation of antiretroviral drug concentration measurements could be aided by information about adherence to recent doses. We developed a population pharmacokinetic model of lamivudine in young children to propose reference lamivudine concentrations for evaluation of adherence to recent treatment doses.Methods: The steady state pharmacokinetics of lamivudine were evaluated in 68 young HIV-infected children receiving antiretroviral treatment twice daily. A population pharmacokinetic analysis was conducted using NONMEM 7.Results: A 2-compartment model with transit absorption best described lamivudine pharmacokinetics. After adjustment for maturation and body weight (using allometric scaling), the variability of clearance was small, hence simulations could accurately predict lamivudine concentrations. Higher lamivudine trough concentrations were detected before the morning dose, possibly owing to slower overnight clearance. Reference values for lamivudine concentrations that can be used to evaluate adherence to recent doses are proposed.Conclusions: Lamivudine concentration measurement can be used to assess recent treatment adherence.
|
|
| 10. |
- Zhang, Chao, et al.
(författare)
-
Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children
- 2012
-
Ingår i: Antiviral Therapy. - 1359-6535 .- 2040-2058. ; 17:1, s. 25-33
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The preferred antiretroviral regimen for young children previously exposed to non-nucleoside reverse transcriptase inhibitors is lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors. Rifampicin-based antitubercular treatment reduces lopinavir concentrations. Adding extra ritonavir to lopinavir/ritonavir overcomes the effect of rifampicin, however this approach is not feasible in many settings. Methods: We developed an integrated population model describing lopinavir and ritonavir pharmacokinetics to predict lopinavir/ritonavir (4:1) doses achieving target lopinavir exposures in children treated for tuberculosis. The model included data from 15 children given 'superboosted' lopinavir (lopinavir/ritonavir = 1:1) and 20 children given twice the standard dose of lopinavir/ritonavir every 12 h during antitubercular treatment, and from children given standard lopinavir/ritonavir doses every 12 h (39 without tuberculosis and 11 sampled again after antitubercular treatment). Results: A one-compartment model with first-order absorption and elimination best described the pharmacokinetics of lopinavir and a one-compartment model with transit absorption compartments described ritonavir pharmacokinetics. The dynamic influence of ritonavir concentration on lopinavir oral clearance was modelled as direct inhibition with an E-max model. Antitubercular treatment reduced the oral bioavailability of lopinavir by 77% in children receiving twice usual lopinavir/ritonavir doses and increased ritonavir clearance by 50%. Simulations predicted that respective 27, 21, 20 and 18 mg/kg 8-hourly doses of lopinavir (in lopinavir/ritonavir, 4: 1) maintains lopinavir concentrations > 1 mg/l in at least 95% of children weighing 3-5.9, 6-9.9, 10-13.9 and 14-19.9 kg. Conclusions: The model describing the interactions between lopinavir, ritonavir and rifampicin in young children predicted feasible 8-hourly doses of lopinavir/ritonavir resulting in therapeutic lopinavir concentrations during antitubercular treatment.
|
|
