Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.

AIMS: Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing. METHODS: The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 µg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0-8, 8-16 and 16-24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling. RESULTS: Mean (95% confidence interval) maximal LSD concentrations were 1.8 ng/mL (1.6-2.0) and 3.4 ng/mL (3.0-3.8) after the administration of 85 and 170 µg LSD, respectively. Maximal concentrations were achieved on average after 1.7 h. Elimination half-lives were 3.7 h (3.4-4.1) and 4.0 h (3.6-4.4), for 85 and 170 µg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2-oxo-3-hydroxy-LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3 ± 3.2 and 11 ± 3.7 h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 µg of LSD, respectively. CONCLUSION: The present novel study validates previous findings. LSD exhibited dose-proportional pharmacokinetics and first-order elimination kinetics and dose-dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose-proportional urinary recovery.

The pharmacokinetics and drug-drug interactions of ivermectin in Aedes aegypti mosquitoes.

Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01-1 µg/ml ivermectin without showing saturation (R2: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI90%: 17.0-19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI90%: 5.1-5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI90%: 8.7-14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods.

Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.

BACKGROUND: Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8-11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD. METHODS: We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours. RESULTS: Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD. CONCLUSIONS: These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy. TRIAL REGISTRY: ClinicalTrials.gov (NCT04558294).

Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes.

BACKGROUND: Ivermectin (22,23-dihydroavermectin B1a: H2B1a) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes. A "post-ivermectin effect" has also been reported, in which the survival of mosquitoes remains reduced even after ivermectin is no longer detectable in blood meals. In the present study, existing material from human clinical trials was analysed to understand the pharmacokinetics of ivermectin metabolites and feeding experiments were performed in Anopheles stephensi mosquitoes to assess whether ivermectin metabolites contribute to the mosquitocidal action of ivermectin and whether they may be responsible for the post-ivermectin effect. METHODS: Ivermectin was incubated in the presence of recombinant human cytochrome P450 3A4/5 (CYP 3A4/5) to produce ivermectin metabolites. In total, nine metabolites were purified by semi-preparative high-pressure liquid chromatography. The pharmacokinetics of the metabolites were assessed over three days in twelve healthy volunteers who received a single oral dose of 12 mg ivermectin. Blank whole blood was spiked with the isolated metabolites at levels matching the maximal blood concentration (Cmax) observed in pharmacokinetics study samples. These samples were fed to An. stephensi mosquitoes, and their survival and vitality was recorded daily over 3 days. RESULTS: Human CYP3A4 metabolised ivermectin more rapidly than CYP3A5. Ivermectin metabolites M1-M8 were predominantly formed by CYP3A4, whereas metabolite M9 (hydroxy-H2B1a) was mainly produced by CYP3A5. Both desmethyl-H2B1a (M1) and hydroxy-H2B1a (M2) killed all mosquitoes within three days post-feeding, while administration of desmethyl, hydroxy-H2B1a (M4) reduced survival to 35% over an observation period of 3 days. Ivermectin metabolites that underwent deglycosylation or hydroxylation at spiroketal moiety were not active against An. stephensi at Cmax levels. Interestingly, half-lives of M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) were considerably longer than that of the parent compound ivermectin (38.9 ± 20.8 h). CONCLUSION: In conclusion, the ivermectin metabolites M1 and M2 contribute to the activity of ivermectin against An. stephensi mosquitoes and could be responsible for the "post-ivermectin effect".

Stimulatory MAIT cell antigens reach the circulation and are efficiently metabolised and presented by human liver cells.

OBJECTIVE: Mucosal-associated invariant T (MAIT) cells are the most abundant T cells in human liver. They respond to bacterial metabolites presented by major histocompatibility complex-like molecule MR1. MAIT cells exert regulatory and antimicrobial functions and are implicated in liver fibrogenesis. It is not well understood which liver cells function as antigen (Ag)-presenting cells for MAIT cells, and under which conditions stimulatory Ags reach the circulation. DESIGN: We used different types of primary human liver cells in Ag-presentation assays to blood-derived and liver-derived MAIT cells. We assessed MAIT cell stimulatory potential of serum from healthy subjects and patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt stent, and patients with inflammatory bowel disease (IBD). RESULTS: MAIT cells were dispersed throughout healthy human liver and all tested liver cell types stimulated MAIT cells, hepatocytes being most efficient. MAIT cell activation by liver cells occurred in response to bacterial lysate and pure Ag, and was prevented by non-activating MR1 ligands. Serum derived from peripheral and portal blood, and from patients with IBD stimulated MAIT cells in MR1-dependent manner. CONCLUSION: Our findings reveal previously unrecognised roles of liver cells in Ag metabolism and activation of MAIT cells, repression of which creates an opportunity to design antifibrotic therapies. The presence of MAIT cell stimulatory Ags in serum rationalises the observed activated MAIT cell phenotype in liver. Increased serum levels of gut-derived MAIT cell stimulatory ligands in patients with impaired intestinal barrier function indicate that intrahepatic Ag-presentation may represent an important step in the development of liver disease.

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine.

AIMS: Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite, 4-methylaminoantipyrine (4-MAA), can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. We aimed to identify the CYPs involved in 4-MAA metabolism and to quantify the effect of CYP inhibition on 4-MAA metabolism. METHODS: We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in male subjects. RESULTS: The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation with CYP2C19 and CYP2D6 contributing to N-demethylation. In the clinical study, we investigated the influence of ciprofloxacin (CYP1A2 inhibitor), fluconazole (CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of metamizole in n = 12 male subjects in a randomized, placebo-controlled, double-blind study. The geometric mean ratios for the area under the concentration-time curve of 4-MAA after/before treatment were 1.17 (90% CI 1.09-1.25) for fluconazole, 1.51 (90% CI 1.42-1.60) for ciprofloxacin and 1.92 (90% CI 1.81-2.03) for ciprofloxacin/fluconazole. Fluconazole increased the half-life of 4-MAA from 3.22 hours by 0.47 hours (95% CI 0.13-0.81, P < .05), ciprofloxacin by 0.69 hours (95% CI 0.44-0.94, P < .001) and fluconazole/ciprofloxacin by 2.85 hours (95% CI 2.48-3.22, P < .001). CONCLUSION: CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. The increase in 4-MAA exposure by the inhibition of CYP1A2 and by the combination CYP1A2/CYP2C19 may be relevant for dose-dependent adverse reactions of 4-MAA.

Effect of deglucuronidation on the results of the Basel phenotyping cocktail.

We investigated the effect of deglucuronidation on the plasma concentration of the constituents of the Basel phenotyping cocktail and on the interpretation of the phenotyping results under basal conditions and after cytochrome P450 (CYP) induction with metamizole. The cocktail containing caffeine (CYP1A2), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A4) was administered to 12 healthy subjects before (basal) and after treatment with metamizole for 1 week. In the basal state, deglucuronidation caused an increase in the plasma concentrations and area under the curve (AUC) of metoprolol, 8'-hydroxyefavirenz, 4'-hydroxyflurbiprofen and 1'-hydroxymidazolam. This effect could be visualized in Bland-Altman plots, where the values for 8'-hydroxyefavirenz, 4'-hydroxyflurbiprofen and 1'-hydroxymidazolam were mostly above the +20% threshold. As a result, the metabolic ratio (MR), calculated as AUCparent drug /AUCmetabolite , decreased with deglucuronidation for CYP2B6, CYP2C9 and CYP3A4 and increased for CYP2D6. Treatment with metamizole, a constitutive androstane receptor-dependent inducer of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, accentuated the effect of deglucuronidation on AUC and MR. The correlation of MRs calculated as the plasma concentration ratio parent drug/metabolite with the MR calculated as the AUC ratio showed that 1 sample obtained between 2 and 6 hours after cocktail ingestion and analysed with and without deglucuronidation is sufficient to obtain reliable phenotyping results. Importantly, CYP2C9 and 3A4 induction would have been missed without deglucuronidation of the plasma samples. In conclusion, deglucuronidation of the plasma samples improves the stability of the phenotyping results of the Basel phenotyping cocktail and is necessary to reliably detect CYP induction.

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans.

AIMS: To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. METHODS: Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract. RESULTS: The geometric mean ratios for the area under the concentration-time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping. CONCLUSION: The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.

The effect of food on the pharmacokinetics of oral ivermectin.

BACKGROUND: Ivermectin is an older anthelminthic agent that is being studied more intensely given its potential for mass drug administration against scabies, malaria and other neglected tropical diseases. Its pharmacokinetics (PK) remain poorly characterized. Furthermore, the majority of PK trials are performed under fasted-state dosing conditions, and the effect of food is therefore not well known. To better plan and design field trials with ivermectin, a model that can account for both conditions would be valuable. OBJECTIVES: To develop a PK model and characterize the food effect with single oral doses of ivermectin. PATIENTS AND METHODS: We performed a population-based PK analysis of data pooled from two previous trials of a single dose of 12 mg ivermectin, one with dosing after a high-fat breakfast (n=12) and one with fasted-state dosing (n=3). RESULTS: The final model described concentration-time profiles after fed and fasted dosing accurately, and estimated the food effect associated with relative bioavailability to 1.18 (95% CI 1.10-1.67). CONCLUSIONS: In this analysis, the effect of a high-fat breakfast compared with a fasted-state administration of a single oral dose of 12 mg ivermectin was minimal.

Pharmacokinetics and phenotyping properties of the Basel phenotyping cocktail combination capsule in healthy male adults.

AIMS: We compared the phenotyping metrics of a combination capsule formulation to its individual components of the newly composed Basel phenotyping cocktail. Moreover, we investigated a reduced sampling regimen for clinical applications. METHODS: We performed in vitro experiments and a crossover pharmacokinetic study in twelve healthy male subjects to compare the Basel phenotyping cocktail capsule containing 6 cytochrome P450 (CYP) probe drugs with individual administration of the same drugs. Parent compounds and selected metabolites were determined by liquid chromatography-tandem mass spectrometry. Metabolic ratios (MR) for are under the curve (AUC) and single time point measurements and their correlation were determined. RESULTS: Experiments with human liver microsomes and primary human hepatocytes in 3D co-culture confirmed that flurbiprofen is a suitable CYP2C9 substrate. Both cocktail formulations (capsule and individual probe drug administration) were well-tolerated and yielded reproducible MRs, which were almost identical. Correlations between single time point ratios and the corresponding AUC ratios depended on the sampling time point and the concentration time curve of the probe drugs. The MR of the capsule (Spearman rank correlation coefficient, Rs : 0.77-0.97) as well as the individual components (Rs : 0.69-0.99) correlated best at 6 h post-treatment considering all 6 CYPs. Moreover, the 2-h time points of the capsule agreed suitably with the AUC; however, the MR of omeprazole could not be determined for 10 out of 12 subjects. CONCLUSION: The capsule is easy to swallow, well tolerated and provides reliable estimates for CYP activity. The optimal sampling point for the capsule formulation is 6 h after intake.

OATP1B3-1B7 (LST-3TM12) Is a Drug Transporter That Affects Endoplasmic Reticulum Access and the Metabolism of Ezetimibe.

Drug transporters play a crucial role in pharmacokinetics. One subfamily of transporters with proven clinical relevance are the OATP1B transporters. Recently we identified a new member of the OATP1B family named OATP1B3-1B7 (LST-3TM12). This functional transporter is encoded by SLCO1B3 and SLCO1B7 OATP1B3-1B7 is expressed in hepatocytes and is located in the membrane of the smooth endoplasmic reticulum (SER). One aim of this study was to test whether OATP1B3-1B7 interacts with commercial drugs. First, we screened a selection of OATP1B substrates for inhibition of OATP1B3-1B7-mediated transport of dehydroepiandrosterone sulfate and identified several inhibitors. One such inhibitor was ezetimibe, which not only inhibited OATP1B3-1B7 but is also a substrate, as its cellular content was significantly increased in cells heterologously expressing the transporter. In humans, ezetimibe is extensively metabolized by hepatic and intestinal uridine-5'-diphospho-glucuronosyltransferases (UGTs), the catalytic site of which is located within the SER lumen. After verification of OATP1B3-1B7 expression in the small intestine, we determined in microsomes whether SER access can be modulated by inhibitors of OATP1B3-1B7. We were able to show that these compounds significantly reduced accumulation in small intestinal and hepatic microsomes, which influenced the rate of ezetimibe ß-D-glucuronide formation as determined in microsomes treated with bromsulphthalein. Notably, this molecule not only inhibits the herein reported transporter but also other transport systems. In conclusion, we report that multiple drugs interact with OATP1B3-1B7; for ezetimibe, we were able to show that SER access and metabolism is significantly reduced by bromsulphthalein, which is an inhibitor of OATP1B3-1B7. SIGNIFICANCE STATEMENT: OATP1B3-1B3 (LST-3TM12) is a transporter that has yet to be fully characterized. We provide valuable insight into the interaction potential of this transporter with several marketed drugs. Ezetimibe, which interacted with OATP1B3-1B7, is highly metabolized by uridine-5'-diphospho-glucuronosyltransferases (UGTs), whose catalytic site is located within the smooth endoplasmic reticulum (SER) lumen. Through microsomal assays with ezetimibe and the transport inhibitor bromsulphthalein we investigated the interdependence of SER access and the glucuronidation rate of ezetimibe. These findings led us to the hypothesis that access or exit of drugs to the SER is orchestrated by SER transporters such as OATP1B3-1B7.

Pharmacokinetics of oxycodone/naloxone and its metabolites in patients with end-stage renal disease during and between haemodialysis sessions.

BACKGROUND: The pharmacokinetics of oxycodone in patients with end-stage renal disease (ESRD) requiring haemodialysis are largely unknown. Therefore, we investigated the pharmacokinetics of oxycodone/naloxone prolonged release and their metabolites in patients with ESRD during and between haemodialysis sessions. METHODS: Single doses of oxycodone/naloxone (5/2.5 or 10/5 mg) were administered in nine patients with ESRD using a cross-over design on the day of dialysis and on a day between dialysis sessions. Plasma, dialysate and urine concentrations of oxycodone, naloxone and their metabolites were determined up to 48 h post-dosing using a liquid chromatography-tandem mass spectrometry system. RESULTS: Haemodialysis performed 6-10 h after dosing removed ∼10% of the administered dose of oxycodone predominantly as unconjugated oxycodone and noroxycodone or conjugated oxymorphone and noroxymorphone. The haemodialysis clearance of oxycodone based on its recovery in dialysate was (mean ± SD) 8.4 ± 2.1 L/h. The geometric mean (coefficient of variation) plasma elimination half-life of oxycodone during the 4-h haemodialysis period was 3.9 h (39%) which was significantly shorter than the 5.7 h (22%) without haemodialysis. Plasma levels of the active metabolite oxymorphone in its unconjugated form were very low. CONCLUSIONS: Oxycodone is removed during haemodialysis. The pharmacokinetics including the relatively short half-life of oxycodone in patients with ESRD with or without haemodialysis and the absence of unconjugated active metabolites indicate that oxycodone can be used at usual doses in patients requiring dialysis.

Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects.

AIMS: The aim of the present study was to characterize the pharmacokinetics and exposure-subjective response relationship of a novel oral solution of lysergic acid diethylamide (LSD) that was developed for clinical use in research and patients. METHOD: LSD (100 µg) was administered in 27 healthy subjects using a placebo-controlled, double-blind, cross-over design. Plasma levels of LSD, nor-LSD, and 2-oxo-3-hydroxy-LSD (O-H-LSD) and subjective drug effects were assessed up to 11.5 hours. RESULTS: First-order elimination kinetics were observed for LSD. Geometric mean maximum concentration (Cmax ) values (range) of 1.7 (1.0-2.9) ng/mL were reached at a tmax (range) of 1.7 (1.0-3.4) hours after drug administration. The plasma half-life (t1/2 ) was 3.6 (2.4-7.3) hours. The AUC∞ was 13 (7.1-28) ng·h/mL. No differences in these pharmacokinetic parameters were found between male and female subjects. Plasma O-H-LSD but not nor-LSD (< 0.01 ng/mL) concentrations could be quantified in all subjects. Geometric mean O-H-LSD Cmax values (range) of 0.11 (0.07-0.19) ng/mL were reached at a tmax (range) of 5 (3.2-8) hours. The t1/2 and AUC∞ values of O-H-LSD were 5.2 (2.6-21) hours and 1.7 (0.85-4.3) ng·h/mL, respectively. The subjective effects of LSD lasted (mean ± SD) for 8.5 ± 2.0 hours (range: 5.3-12.8 h), and peak effects were reached 2.5 ± 0.6 hours (range 1.6-4.3 h) after drug administration. EC50 values were 1.0 ± 0.5 ng/mL and 1.9 ± 1.0 ng/mL for "good" and "bad" subjective drug effects, respectively. CONCLUSION: The present study characterized the pharmacokinetics of LSD and its main metabolite O-H-LSD. The subjective effects of LSD were closely associated with changes in plasma concentrations over time.

Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers.

AIMS: The anthelminthic ivermectin is receiving new attention as it is being repurposed for new indications such as mass drug administrations for the treatment of scabies or in malaria vector control. As its pharmacokinetics are still poorly understood, we aimed to characterize the population pharmacokinetics of ivermectin in plasma and dried blood spots (DBS), a sampling method better suited to field trials, with special focus on the influence of body composition and enterohepatic circulation. METHODS: We performed a clinical trial in 12 healthy volunteers who each received a single oral dose of 12 mg ivermectin, and collected peripheral venous and capillary DBS samples. We determined ivermectin concentrations in plasma and DBS by liquid chromatography tandem mass spectrometry using a fully automated and scalable extraction system for DBS sample processing. Pharmacokinetic data were analysed using non-linear mixed effects modelling. RESULTS: A two-compartment model with a transit absorption model, first-order elimination, and weight as an influential covariate on central volume of distribution and clearance best described the data. The model estimates (inter-individual variability) for a 70 kg subject were: apparent population clearance 7.7 (25%) l h-1 , and central and peripheral volumes of distribution 89 (10%) l and 234 (20%) l, respectively. Concentrations obtained from DBS samples were strongly linearly correlated (R2  = 0.97) with plasma concentrations, and on average 30% lower. CONCLUSION: The model accurately depicts population pharmacokinetics of plasma and DBS concentrations over time for oral ivermectin. The proposed analytical workflow is scalable and applicable to the requirements of mass drug administrations.

Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study.

PURPOSE: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3-72 months. METHODS: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC0-inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3-23 months, 2-6 years) and compared with the 80-125% range of adult dose-adjusted reference exposure (AUCref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. RESULTS: A total of 25 children aged 5 months-5.8 years (7.8-24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUCref (80-125% range 39.2-61.2 mg/L/h). AUC0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUCref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. CONCLUSIONS: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight-based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10-20 mg/kg) to achieve equivalent adult exposure. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02660177 .

PGC-1ß modulates statin-associated myotoxicity in mice.

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1ß expression in human and rat skeletal muscle, suggesting that PGC-1ß may play a role in statin-induced myopathy. PGC-1ß is a transcriptional co-regulator controlling the expression of important genes in mitochondrial biogenesis, antioxidative capacity and energy metabolism. The principle aim of the current study was to investigate the interaction between atorvastatin and PGC-1ß in more detail. We therefore treated wild-type mice and mice with selective skeletal muscle knockout of PGC-1ß (PGC-1ß(i)skm-/- mice) with oral atorvastatin (5 mg/kg/day) for 2 weeks. At the end of treatment, we determined body parameters, muscle function, structure, and composition as well as the function of muscle mitochondria, mitochondrial biogenesis and activation of apoptotic pathways. In wild-type mice, atorvastatin selectively impaired mitochondrial function in glycolytic muscle and caused a conversion of oxidative type IIA to glycolytic type IIB myofibers. Conversely, in oxidative muscle of wild-type mice, atorvastatin enhanced mitochondrial function via activation of mitochondrial biogenesis pathways and decreased apoptosis. In PGC-1ß(i)skm-/- mice, atorvastatin induced a switch towards glycolytic fibers, caused mitochondrial dysfunction, increased mitochondrial ROS production, impaired mitochondrial proliferation and induced apoptosis in both glycolytic and oxidative skeletal muscle. Our work reveals that atorvastatin mainly affects glycolytic muscle in wild-type mice and demonstrates the importance of PGC-1ß for oxidative muscle integrity during long-term exposure to a myotoxic agent.

Using dried blood spots to facilitate therapeutic drug monitoring of antiretroviral drugs in resource-poor regions.

Objectives: We evaluated whether dried blood spots (DBS) are suitable to monitor combined ART when samples are collected in rural Tanzania and transported over a long distance to a specialized bioanalytical laboratory. Methods: Plasma and DBS samples were collected in Tanzania from study patients treated with nevirapine, efavirenz or lopinavir. In addition, plasma, whole blood and DBS samples were obtained from a cohort of HIV patients at the site of the bioanalytical laboratory in Switzerland. DBS samples were analysed using a fully automated LC-MS/MS method. Results: Comparison of DBS versus plasma concentrations of samples obtained from the bridging study in Switzerland indicated an acceptable bias only for nevirapine (18.4%), whereas for efavirenz and lopinavir a pronounced difference of -47.4% and -48.1% was found, respectively. Adjusting the DBS concentrations by the haematocrit and the fraction of drug bound to plasma proteins removed this bias [efavirenz +9.4% (-6.9% to +25.7%), lopinavir +2.2% (-20.0% to +24.2%)]. Storage and transportation of samples from Tanzania to Switzerland did not affect the good agreement between plasma and DBS for nevirapine [-2.9% (-34.7% to +29.0%)] and efavirenz [-9.6% (-42.9% to +23.8%)]. For lopinavir, however, adjusted DBS concentrations remained considerably below [-32.8% (-70.4% to +4.8%)] corresponding plasma concentrations due to decay of lopinavir in DBS obtained under field conditions. Conclusions: Our field study shows that the DBS technique is a suitable tool for therapeutic drug monitoring in resource-poor regions; however, sample stability remains an issue for certain analytes and therefore needs special consideration.

Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults.

There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.).

Single-Ascending-Dose Pharmacokinetic Study of Tribendimidine in Opisthorchis viverrini-Infected Patients.

Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (Tmax) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) of dADT to the AUC0- 24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (Cmax) and AUC0-24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.).

Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects.

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a popular recreational drug. The aim of the present study was to explore the role of dopamine in the psychotropic effects of MDMA using bupropion to inhibit the dopamine and norepinephrine transporters through which MDMA releases dopamine and norepinephrine by investigating. The pharmacodynamic and pharmacokinetic interactions between bupropion and MDMA in 16 healthy subjects were investigated using a double-blind, placebo-controlled, crossover design. Bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA. In contrast, bupropion increased plasma MDMA concentrations and prolonged its subjective effects. Conversely, MDMA increased plasma bupropion concentrations. These results indicate a role for the transporter-mediated release of norepinephrine in the cardiostimulant effects of MDMA but do not support a modulatory role for dopamine in the mood effects of MDMA. These results also indicate that the use of MDMA during therapy with bupropion may result in higher plasma concentrations of both MDMA and bupropion and enhanced mood effects but also result in lower cardiac stimulation.