| 1. |
- Ahlström, Christine, et al.
(författare)
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Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions
- 2011
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Ingår i: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS. - 1567-567X. ; 38:1, s. 1-24
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Tidskriftsartikel (refereegranskat)abstract
- A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg(-1) of body weight) or over 300 min (0, 5, 10 or 51 μmol kg(-1) of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M (1)) inhibited the formation of R and the last compartment (M ( N )) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC (50), of NiAc was 45 nmol L(-1), the fractional turnover rate k ( out ) was 0.41 L mmol(-1) min(-1) and the turnover rate of moderator k ( tol ) was 0.027 min(-1). A lower physiological limit of NEFA was modeled as a NiAc-independent release (k ( cap )) of NEFA into plasma and was estimated to 0.032 mmol L(-1) min(-1). This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.
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| 2. |
- Amilon, Carl, et al.
(författare)
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Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy
- 2022
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Ingår i: The AAPS journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 24:3
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Tidskriftsartikel (refereegranskat)abstract
- (Carl Amilon and Mikael Boberg contributed equally to this work) Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.
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| 3. |
- Boberg, Mikael, et al.
(författare)
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Chiral Chromatographic Isolation on Milligram Scale of the Human African Trypanosomiasis Treatment D- and L-Eflornithine.
- 2020
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Ingår i: ACS omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:37, s. 23885-23891
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Tidskriftsartikel (refereegranskat)abstract
- Eflornithine is a recommended treatment against the otherwise fatal parasitic disease late stage human African trypanosomiasis (HAT), also known as Gambian sleeping sickness. It is administered repeatedly as a racemic mixture intravenously (IV) together with oral nifurtimox. Racemic eflornithine has been investigated in clinical trials for oral dosing. However, due to low systemic exposures at a maximum tolerated oral dose, the drug is continued to be administered IV. The eflornithine enantiomers, D- and L-eflornithine, have different affinities to the target enzyme ornithine decarboxylase, suggesting that the pharmacodynamics of the enantiomers may differ. The aim of this study was to develop a method for isolation of d- and l-eflornithine from a racemic mixture. Several chiral stationary phases (CSPs) were evaluated for enantioselectivity using supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC). None of the tested CSPs rendered separation of the enantiomers in SFC mode. Separation of the enantiomers with SFC on the CSP Chiralpak IG was only achieved on an analytical scale after derivatization with ortho-phthalaldehyde (OPA). This was the first reported enantioselective SFC method for an eflornithine derivate. However, due to poor stability, the eflornithine-OPA derivates degraded and no chemically pure enantiomers were obtained. The CSP that showed enantioselectivity in HPLC mode was Chirobiotic R, which resulted in a successful isolation on a semipreparative milligram scale. The isolated eflornithine enantiomers will be tested in nonclinical in vitro and in vivo studies to support and assess the feasibility of a future clinical program with an oral HAT treatment.
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| 4. |
- Boberg, Mikael, et al.
(författare)
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Enantiospecific antitrypanosomal in vitro activity of eflornithine. : L-eflornithine against human African trypanosomiasis
- 2021
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2735. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 μM (95% confidence interval [8.1; 10]), 5.5 μM [4.5; 6.6], and 50 μM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.
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| 5. |
- Jansson Löfmark, Rasmus, 1979, et al.
(författare)
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Determination of eflornithine enantiomers in plasma by precolumn derivatization with o-phthalaldehyde-N-acetyl-l-cysteine and liquid chromatography with UV detection
- 2010
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Ingår i: BMC Biomedical chromotography. - : Wiley. - 0269-3879 .- 1099-0801. ; 24:7, s. 768-773
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Tidskriftsartikel (refereegranskat)abstract
- A bioanalytical method for indirect determination of eflornithine enantiomers in 75 mu L human plasma has been developed and validated. L- and D-eflornithine were derivatized with o-phthalaldehyde and N-acetyl-L-cysteine to generate diastereomers which were separated on two serially connected Chromolith Performance columns (RP-18e 100 x 4.6 mm i.d.) by a isocratic flow followed by a gradient flow for elution of endogenous compounds. The diastereomers were detected with UV (340 nm). The between-day precisions for L- and D-eflornithine in plasma were 8.4 and 2.3% at 3 mu m, 4.0 and 5.1% at 400 mu m, and 2.0 and 3.7% at 1000 mu m. The lower limit of quantification was determined to be 1.5 mu m, at which precision was 14.9 and 9.9% for 1- and D-eflornithine, respectively.
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| 6. |
- Jansson Löfmark, Rasmus, 1979, et al.
(författare)
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Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness
- 2015
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 59:2, s. 1299-1307
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to characterize the stereoselective pharmacokinetics of oral eflornithine in 25 patients with late-stage Trypanosoma brucei gambiense sleeping sickness. A secondary aim was to determine the concentrations of L-and D-eflornithine required in plasma or cerebrospinal fluid (CSF) for an efficient eradication of the T. brucei gambiense parasites. Patients were randomly allocated to receive either 100 (group I, n = 12) or 125 (group II, n = 13) mg/kg of body weight of drug every 6 h for 14 days. The concentrations of L-and D-eflornithine in the plasma and CSF samples were measured using a stereospecific liquid chromatographic method. Nonlinear mixed-effects modeling was used to characterize the plasma pharmacokinetics. The plasma concentrations of L-eflornithine were on average 52% (95% confidence interval [CI], 51, 54%; n = 321) of the D-enantiomer concentrations. The typical oral clearances of L-and D-eflornithine were 17.4 (95% CI, 15.5, 19.3) and 8.23 (95% CI, 7.36, 9.10) liters/h, respectively. These differences were likely due to stereoselective intestinal absorption. The distributions of eflornithine enantiomers to the CSF were not stereoselective. A correlation was found between the probability of cure and plasma drug exposure, although it was not more pronounced for the L-enantiomer than for that of total eflornithine. This study may explain why oral treatment for late-stage human African trypanosomiasis (HAT) patients with racemic eflornithine has previously failed; the more potent L-enantiomer is present at much lower concentrations in both plasma and CSF than those of the D-enantiomer. Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further.
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| 7. |
- Jansson Löfmark, Rasmus, 1979
(författare)
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On the Stereoselective Pharmacokinetics of Eflornithine and Prediction of Drug Tissue to Plasma Concentration Ratios
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Eflornithine is one of two registered drugs for the treatment of late-stage human African trypanosomiasis, a uniformly fatal neglected disease with sixty million people are at risk of being infected. Eflornithine is efficacious but the cumbersome intravenous administration leaves numerous patients untreated. A simplified mode of administration, preferably oral, would enable more patients having access to treatment. The trypanostatic agent eflornithine is administered as a racemate where the L – form has a several-fold greater in vitro potency compared to the D – enantiomer. Despite the difference in potency of the enantiomers, the stereoselective pharmacokinetics of eflornithine has not been considered. This thesis aimed to study L – and D – eflornithine pharmacokinetics in the rat, in Caco-2 cells and in late-stage human African Trypanosomiasis patients. A secondary aim was also to develop a general method for predicting drug tissue to plasma concentration ratios. In the rat, eflornithine displayed stereoselective absorption where the more potent L – form had an approximately 50% lower fraction absorbed compared to D – eflornithine. The stereoselective mechanism was not detected in the present Caco-2 cell assay. Late-stage HAT patients, treated with racemic oral eflornithine, had an approximate 50% lower exposure of L – compared to D – eflornithine, similar to those in rat. The findings suggested that previous attempts to develop an oral eflornithine dosage regimen have failed due to unfavorable stereoselective absorption. High plasma exposure for both L – and D – eflornithine were significantly correlated to the probability of being cured. For the secondary aim of this thesis, the novel method to predict drug tissue distribution, based on a measured volume of distribution in combination with drug lipophilicity performed reasonably well. Predicted drug tissue to plasma concentration ratios agreed reasonably well with experimentally determined values with 85% being within a factor of ±3 to experimental values (n=148). In conclusion, this thesis present the stereoselective pharmacokinetics of eflornithine that can give information on whether a much needed oral eflornithine can be developed or not. In addition, the thesis also presents a general method to predict drug tissue to plasma concentration ratios.
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| 8. |
- Johansson, Carl-Christer, et al.
(författare)
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Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat.
- 2013
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Ingår i: Journal of pharmacokinetics and pharmacodynamics. - : Springer Science and Business Media LLC. - 1573-8744 .- 1567-567X. ; 40:1, s. 117-28
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Tidskriftsartikel (refereegranskat)abstract
- Enantioselective pharmacokinetics and absorption of eflornithine in the rat was investigated using population pharmacokinetic modeling and a modified deconvolution method. Bidirectional permeability of L- and D-eflornithine was investigated in Caco-2 cells. The rat was administered racemic eflornithine hydrochloride as a single oral dose [40-3,000 mg/kg bodyweight (BW)] or intravenously (IV) (100-2,700 mg/kg BW infused over 60-400 min). Serial arterial blood samples were collected and L- and D-eflornithine were quantitated with a previously published chiral bioanalysis method. The D:L concentration ratio was determined in rat faeces. Intravenous L-and D-eflornithine plasma concentration-time data was analyzed using population pharmacokinetic modeling and described with a 3-compartment pharmacokinetic model with saturable binding to one of the peripheral compartments. Oral plasma concentration-time data was analyzed using a modified deconvolution method accounting for nonlinearities in the eflornithine pharmacokinetics. Clearance was similar for both enantiomers (3.36 and 3.09 mL/min). Oral bioavailability was estimated by deconvolution at 30 and 59% for L- and D-eflornithine. The D:L concentration ratio in feces was 0.49 and the Caco-2 cell permeability was similar for both enantiomers (6-10 × 10(-8) cm/s) with no evident involvement of active transport or efflux. The results presented here suggest that the difference in the bioavailability between eflornithine enantiomers is caused by a stereoselective difference in extent rather than rate of absorption. The presented modified deconvolution method made it possible to account for the non-linear component in the suggested three-compartment pharmacokinetic model thus rapidly estimating eflornithine oral bioavailability.
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