| 1. |
- Birgersson, Sofia, 1976, et al.
(författare)
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Population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers
- 2016
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artemisinin-based combination therapy is recommended as first-line anti-malarial treatment worldwide. A combination of artemisinin with the long acting drug piperaquine has shown high efficacy and tolerability in patients with uncomplicated Plasmodium falciparum infections. The aim of this study was to characterize the population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers after two different dose sizes, formulations and in a combination with piperaquine. A secondary aim was to compare two different methods for the evaluation of bioequivalence of the formulations. Methods: Fifteen subjects received four different dose regimens of a single dose of artemisinin as a conventional formulation (160 and 500 mg) and as a micronized test formulation (160 mg alone and in combination with piperaquine phosphate, 360 mg) with a washout period of 3 weeks between each period (i.e. four-way cross-over). Venous plasma samples were collected frequently up to 12 h after dose in each period. Artemisinin was quantified in plasma using liquid chromatography coupled with tandem mass spectrometry. A nonlinear mixed-effects modelling approach was utilized to evaluate the population pharmacokinetic properties of the drug and to investigate the clinical impact of different formulations. Results: The plasma concentration-time profiles for artemisinin were adequately described by a transit-absorption model with a one-compartment disposition, in all four sequences simultaneously. The mean oral clearance, volume of distribution and terminal elimination half-life was 417 L/h, 1210 L and 1.93 h, respectively. Influence of formulation, dose and possible interaction of piperaquine was evaluated as categorical covariates in full covariate approaches. No clinically significant differences between formulations were shown which was in accordance with the previous results using a non-compartmental bioequivalence approach. Conclusions: This is the first population pharmacokinetic characterization of artemisinin in healthy volunteers. Increasing the dose resulted in a significant increase in the mean transit-time but the micronized formulation or concomitant piperaquine administration did not affect the pharmacokinetic properties of artemisinin. The results from the traditional bioequivalence evaluation were comparable with results obtained from mixed-effects modelling.
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| 2. |
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| 3. |
- Höglund, Richard, 1984, et al.
(författare)
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Artemether-lumefantrine coadministration with antiretrovirals; population pharmacokinetics and dosing implications
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 79:4, s. 636-649
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Tidskriftsartikel (refereegranskat)abstract
- AimDrug-drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug-drug interactions between the anti-malarial drugs; lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV-drugs efavirenz, nevirapine and lopinavir/ritonavir.Method Data from two clinical studies, investigating the influence of the HIV-drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analysed using a nonlinear mixed-effects modelling approach.ResultsEfavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.Conclusion There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV coinfected patients.
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| 4. |
- Rekić, Dinko, 1984, et al.
(författare)
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External Validation of the Bilirubin-Atazanavir Nomogram for Assessment of Atazanavir Plasma Exposure in HIV-1-Infected Patients.
- 2013
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Ingår i: The AAPS journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 15:2, s. 308-15
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Tidskriftsartikel (refereegranskat)abstract
- Atazanavir increases plasma bilirubin levels in a concentration-dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work, a previously developed nomogram for detection of suboptimal atazanavir exposure is validated against external patient populations. The bilirubin nomogram was validated against 311 matching bilirubin and atazanavir samples from 166 HIV-1-infected Norwegian, French, and Italian patients on a ritonavir-boosted regimen. In addition, the nomogram was evaluated in 56 Italian patients on an unboosted regimen. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. The use of the nomogram to detect non-adherence was also investigated by simulation. The bilirubin nomogram predicted suboptimal exposure in the patient populations on a ritonavir-boosted regimen with a negative predictive value of 97% (95% CI 95-100). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during a period of non-adherence, they had lower predictive power to detect past non-adherence episodes. Using the bilirubin nomogram for detection of suboptimal atazanavir exposure in patients on a ritonavir-boosted regimen is a rapid and cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings if atazanavir concentrations are not available.
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| 5. |
- Singtoroj, T, et al.
(författare)
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A new approach to evaluate regression models during validation of bioanalytical assays
- 2006
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Ingår i: J Pharm Biomed Anal. - : Elsevier BV. ; 41:1, s. 219-227
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Tidskriftsartikel (refereegranskat)abstract
- The quality of bioanalytical data is highly dependent on using an appropriate regression model for calibration curves. Non-weighted linear regression has traditionally been used but is not necessarily the optimal model. Bioanalytical assays generally benefit from using either data transformation and/or weighting since variance normally increases with concentration. A data set with calibrators ranging from 9 to 10000 ng/mL was used to compare a new approach with the traditional approach for selecting an optimal regression model. The new approach used a combination of relative residuals at each calibration level together with precision and accuracy of independent quality control samples over 4 days to select and justify the best regression model. The results showed that log-log transformation without weighting was the simplest model to fit the calibration data and ensure good predictability for this data set.
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| 6. |
- Tärning, Joel, 1977, et al.
(författare)
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Characterization of Human Urinary Metabolites of the Antimalarial Piperaquine
- 2006
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 34, s. 2011-9
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Tidskriftsartikel (refereegranskat)abstract
- Five metabolites of the antimalarial piperaquine (PQ) (1,3-bis-[4-(7chloroquinolyl-4)-piperazinyl-1]-propane) have been identified and their molecular structures characterized. After a p.o. dose of dihydroartemisinin-piperaquine, urine collected over 16 h from two healthy subjects was analyzed using liquid chromatography (LC)/UV, LC/tandem mass spectrometry (MS/MS), Fourier transform ion cyclotron resonance (FTICR)/MS, and H NMR. Five different peaks were recognized as possible metabolites [M1, 320 m/z; M2, M3, and M4, 551 m/z (PQ + 16 m/z); and M5, 567 m/z (PQ + 32 m/z)] using LC/MS/MS with gradient elution. The proposed carboxylic M1 has a theoretical monoisotopic molecular mass of 320.1166 m/z, which is in accordance with the FTICR/MS (320.1168 m/z) findings. The LC/MS/MS results also showed a 551 m/z metabolite (M2) with a distinct difference both in polarity and fragmentation pattern compared with PQ, 7-hydroxypiperaquine, and the other 551 m/z metabolites. We suggest that this is caused by N-oxidation of PQ. The results showed two metabolites (M3 and M4) with a molecular ion at 551 m/z and similar fragmentation pattern as both PQ and 7-hydroxypiperaquine; therefore, they are likely to be hydroxylated PQ metabolites. The molecular structures of M1 and M2 were also confirmed using H NMR. Urinary excretion rate in one subject suggested a terminal elimination half-life of about 53 days for M1. Assuming formation rate-limiting kinetics, this would support recent findings that the terminal elimination half-life of PQ has been underestimated previously.
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| 7. |
- Tärning, Joel, 1977, et al.
(författare)
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Development and validation of an automated solid phase extraction and liquid chromatographic method for the determination of piperaquine in urine
- 2006
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Ingår i: J Pharm Biomed Anal. - : Elsevier BV. ; 41:1, s. 213-218
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Tidskriftsartikel (refereegranskat)abstract
- A sensitive and specific bioanalytical method for determination of piperaquine in urine by automated solid-phase extraction (SPE) and liquid chromatography (LC) has been developed and validated. Buffered urine samples (containing internal standard) were loaded onto mixed phase (cation-exchange and octylsilica) SPE columns using an ASPEC XL SPE robot. Chromatographic separation was achieved on a Chromolith Performance RP-18e (100 mm x 4.6 mm I.D.) LC column with phosphate buffer (pH 2.5; 0.1 mol/L)-acetonitrile (92:8, v/v). Piperaquine was analysed at a flow rate of 3 mL/min with UV detection at 347 nm. A linear regression model on log-log transformed data was used for quantification. Within-day precision for piperaquine was 1.3% at 5000 ng/mL and 6.6% at 50 ng/mL. Between-day precision for piperaquine was 3.7% at 5000 ng/mL and 7.2% at 50 ng/mL. Total-assay precision for piperaquine over 4 days using five replicates each day (n = 20) was 4.0%, 5.2% and 9.8% at 5000, 500 and 50 ng/mL, respectively. The lower limit of quantification (LLOQ) was set to 3 ng/mL using 1 mL of urine, which could be lowered to 0.33 ng/mL when using 9 mL of urine and an increased injection volume.
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| 8. |
- Tärning, Joel, 1977, et al.
(författare)
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Pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat.
- 2008
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Ingår i: Journal of pharmaceutical sciences. - : Elsevier BV. - 1520-6017 .- 0022-3549. ; 97:8, s. 3400-10
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to evaluate the pharmacokinetic properties of piperaquine in the rat after intravenous and oral administration, and to identify and characterize the main piperaquine metabolites in rat plasma, urine, faeces and bile after intravenous administration. Male Sprague-Dawley rats were administered piperaquine as an emulsion orally or as a short-term intravenous infusion. Venous blood for pharmacokinetic evaluation was frequently withdrawn up to 90 h after dose. Urine, bile and faeces were collected after an infusion in rats kept in metabolic cages or in anesthetized rats. Pharmacokinetic characterization was done by compartmental modeling and non-compartmental analysis using WinNonlin. Piperaquine disposition was best described by a 3-compartment model with a rapid initial distribution phase after intravenous administration. The pharmacokinetics of piperaquine was characterized by a low clearance, a large volume of distribution and a long terminal half-life. Piperaquine displayed a low biliary clearance and less than 1% of the total dose was recovered in urine. The absolute oral bioavailability was approximately 50%. The main metabolite after intravenous administration of piperaquine was a carboxylic acid product identical to that reported in humans. The similarity with results in humans indicates the rat to be a suitable species for nonclinical in vivo piperaquine studies.
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| 9. |
- Tärning, Joel, 1977
(författare)
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Piperaquine - Bioanalys, drug metabolism and pharmacokinetics
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malaria is one of the most abundant parasitic diseases in the world affecting many of the poorest economies. The estimated prevalence is 300 to 700 million clinical episodes each year with up to 3 million deaths. Piperaquine replaced chloroquine as the first line treatment in China for Plasmodium falciparum malaria in the 1970s and was used as mass prophylaxis until the emergence of resistance in the 1990s. It has recently been the object of renewed interest as a partner drug in artemisinin-based combination therapy. Artekin® is a fixed oral combination of dihydroartemisinin and piperaquine showing excellent efficacy and tolerability against multi-resistant Plasmodium falciparum malaria. Only a limited number of studies have addressed the clinical pharmacokinetics of piperaquine, none of which have addressed metabolism. Despite its extensive use no published information is available about the non-clinical pharmacokinetics or drug metabolism in animals. The bioanalytical tools used in this thesis were nuclear magnetic resonance, liquid chromatography, quantitative and qualitative mass spectrometry. Data analysis was conducted using conventional statistics, population based pharmacokinetic modeling, individual pharmacokinetic modeling and non-compartmental analysis. The results present a new systematic approach for choosing a regression model during bioanalytical method validation that can be a useful tool for finding the optimal regression model (paper I). It incorporates predictability of independent quality control samples as well as the calibration curve fit. This approach was used to find the best regression model during the development and validation of a sensitive and selective bioanalytical method for quantification of piperaquine in urine by automated solid-phase extraction and isocratic liquid chromatography (paper II). Five human urinary metabolites of piperaquine were identified and their molecular structures characterized in two healthy male volunteers after an oral single dose of the dihydroartemisinin-piperaquine combination (paper III). The major metabolites are a carboxyl acid cleavage product and a N-oxidated piperaquine product. The rat appears to be a suitable animal model for non-clinical in vivo studies since piperaquine pharmacokinetic properties and metabolites are similar to those found in humans (paper IV). The absolute oral bioavailability was estimated to approximately 50%. The low between-animal variability in plasma concentrations after intravenous administration suggests absorption to be critical for between-animal variability in drug exposure. Piperaquine displayed a low biliary clearance with less than 1% of the total dose excreted by this route. Enterohepatic circulation would not contribute significantly to a prolongation of the terminal half-life. Piperaquine elimination half-life might be underestimated due to inadequate assay sensitivity and/or duration of sampling in published information (paper V). This should be considered when establishing the duration of follow-up and the assessment of relapse in clinical studies. The population pharmacokinetics of piperaquine was characterized in 98 patients in Thailand with uncomplicated Plasmodium falciparum malaria, ranging from 3 to 55 years of age (paper VI). The study confirms that piperaquine exhibits considerable inter-individual pharmacokinetic variability, has a very large apparent volume of distribution, and a slow elimination phase. Pharmacokinetic modeling suggests that despite having a smaller central volume of distribution and slower elimination than adults, the children in this study had lower piperaquine concentrations in the therapeutically important period immediately following treatment. If this is confirmed in other malaria affected regions, then consideration should be given to increase the weight adjusted dosage in children. No pharmacokinetic differences could be seen between the two investigated study treatment regimens and further support the use of a simplified, once daily treatment, regimen to improve treatment adherence and efficacy. Overall, this thesis has contributed to a better understanding of the bioanalysis, drug metabolism and pharmacokinetics of piperaquine which may contribute to its future safe and efficacious clinical use as an antimalarial.
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| 10. |
- Tärning, Joel, 1977, et al.
(författare)
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Pitfalls in estimating piperaquine elimination
- 2005
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Ingår i: Antimicrob Agents Chemother. ; 49, s. 5127-8
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Tidskriftsartikel (refereegranskat)abstract
- By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.
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