Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin

A four compartment mechanistic mathematical model is developed for the pharmacokinetics of the commonly used anti-malarial drug artesunate and its principle metabolite dihydroartemisinin following oral administration of artesunate. The model is structurally unidentifiable unless additional constraints are imposed. Combinations of mechanistically derived constraints are considered to assess their effects on structural identifiability and on model fits. Certain combinations of the constraints give rise to locally or globally identifiable model structures. Initial validation of the model under various combinations of the constraints leading to identifiable model structures was performed against a dataset of artesunate and dihydroartemisinin concentration–time profiles of 19 malaria patients. When all the discussed constraints were imposed on the model, the resulting globally identifiable model structure was found to fit reasonably well to those patients with normal drug absorption profiles. However, there is wide variability in the fitted parameters and further investigation is warranted

Pharmacokinetic modelling and development of Bayesian estimators for therapeutic drug monitoring of mycophenolate mofetil in reduced-intensity haematopoietic stem cell transplantation.

International audienceBACKGROUND: Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical. OBJECTIVES: To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT. PATIENTS AND METHODS: Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. RESULTS: The ITS approach allowed the development of MAP-BEs based either on 'double-gamma' or 'triple-gamma' models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data. CONCLUSION: Pharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations

Acute pain in domestic cats : nociceptive investigation and novel therapeutics

La disponibilité des médicaments analgésiques est limitée en médecine vétérinaire féline. Le but de cette étude était d'investiguer les propriétés anti-nociceptiques d'une nouvelle formule de buprénorphine (Simbadol, 1.8 mg ml-1) et tapentadol chez les chats. Six chats étaient inclus dans deux études différentes, les deux étant prospectives, randomisées, croisées, et aveuglées. Dans la première étude, Simbadol (1.8 mg mL-1) a été administré par voies sous-cutanée (SC;0.24 mg kg-1), intraveineuse (IV; 0.12 mg kg-1) et buccale (OTM; 0.12 mg kg-1) et les seuils thermiques ont été comparés avec ceux d'un groupe contrôle contenant de la saline (SAL; saline SC). Les concentrations plasmatiques de buprénorphine et norbuprénorphine ont été mesurées jusqu'à 72 heures suivant chaque traitement de buprénorphine. Un modèle pharmacocinétique-pharmacodynamique adapté à 2 substances et 3 voies d'administration a été utilisé. Dans la deuxième étude, les seuils thermiques ont été comparés entre les chats recevant de la buprénorphine (0.02 mg kg−1, IM), un placébo (50 mg de dextrose oral) et deux doses de tapentadol oralement (dose réduite: 25 mg; dose élevée: 50 mg) L'administration sous-cutanée de Simbadol a provoqué une anti-nociception thermique de longue durée (≥ 24 heures). Ces effets étaient prolongés comparativement aux traitements intraveineux (8 heures) et buccal (12 heures). Le modèle conjoint de pharmacocinétique/pharmacodynamique a démontré des concentrations plasmatiques prolongée pour la voie sous-cutanée. Les deux doses de tapentadol ont augmenté l'antinociception thermique chez les chats. La dose élevée de tapentadol a produit une durée d'antinociception similaire à celle de la buprénorphine (2 heures) et deux fois plus longue que la dose réduite. La palatabilité de la médication représente une limite significative de la voie d'administration. Simbadol et tapentadol produisent une antinociception thermique comparée à la saline. Des investigations cliniques supplémentaires seront nécessaires.Analgesic drug availability is limited in feline practice. The aim of these studies was to investigate the antinociceptive properties of a novel formulation of buprenorphine (Simbadol, 1.8 mg ml-1) and tapentadol in cats. In two separate studies, six healthy cats (each) were included in a prospective, randomised, blinded, crossover study. In study I, Simbadol (1.8 mg mL-1) was administered by various routes: subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL; saline SC). Plasma buprenorphine and norbuprenorphine concentrations were measured up to 72 hours following each buprenorphine treatment. A bespoke pharmacokinetic-pharmacodynamic model fitted data from two analytes/three routes of administration. In study II, thermal thresholds were compared among cats receiving buprenorphine (0.02 mg kg−1, IM), placebo (50 mg oral dextrose) and two doses of oral tapentadol (low-dose 25 mg; high-dose 50 mg). Subcutaneous administration of Simbadol provided long-lasting thermal antinociception (≥ 24 hours). These effects are prolonged compared with the IV (8 hours) and OTM (12 hours) treatments. Joint pharmacokinetic-pharmacodynamic modelling demonstrated prolonged plasma concentrations for the SC route. Both doses of tapentadol increased thermal antinociception in cats. The high-dose of tapentadol produced similar duration of antinociception as intramuscular buprenorphine (2 hours) and twice as long as the low-dose. Palatability presented a significant limitation to the drug’s administration. Simbadol and tapentadol produced thermal antinociception when compared with saline. Additional investigation is necessary to determine if this translates to the clinical setting

Impact of Augmented Renal Clearance in Critically Ill Patients: Population Pharmacokinetics of Levetiracetam and Dosing Evaluation

145 p.Introduction: Augmented renal clearance (ARC) is a phenomenon recently identified in critically ill patients.ARC has the potential to influence the pharmacokinetic profile of any drug that is renally cleared andknown to have a direct correlation between renal clearance (CL) and creatinine clearance (CrCl), such aslevetiracetam. Objective: The aim of this thesis was initially to evaluate the adequacy of levetiracetamdosing for the achievement of therapeutic levels in patients with normal or high renal clearance admittedto the ICU by the characterization of its pharmacokinetics by population modelling and simulation.Alternative dosage regimens able to achieve target concentrations in this population have been alsoproposed using stochastic simulations and considering biopharmaceutical and pharmacokinetic aspects.Methods: A systematic review on ARC phenomenon was conducted. A multicentre prospective study incritically ill patients treated with levetiracetam was carried out. A population pharmacokinetic model oflevetiracetam in critically ill patients was developed. Alternative dosage regimens were evaluated byMonte Carlo simulation. Results and discussion: The systematic review showed that ARC, defined as a CrCl>130 mL/min/1.73 m2 measured in urine, is present in 20 to 65% of critically ill patients, being youngerage, polytrauma and lower severity illness identified risk factors. Twenty-seven critically ill patients wereincluded in the pharmacokinetic study. A two-compartment model best described levetiracetampharmacokinetics in this population, only CrCl was found to be a significant covariate of its CL. In criticallyill patients with ARC conventional dosage regimens (500-1500 mg twice daily in a short infusion) do notallow to obtain trough plasma concentrations in the defined target, between 12 and 46mg/L. Newdosage regimens to be implemented in critically ill patients with ARC were proposed by using MonteCarlo simulations based on the population pharmacokinetic model developed and consideringbiopharmaceutical and pharmacokinetics aspects

Modelling and simulation techniques to investigate pharmacokinetics, pharmacodynamics, and drug-drug interactions

Modelling and simulation (M&S) techniques can support characterisation and understanding of pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interactions (DDI) of drugs, therewith supporting dosing strategies during drug development and regulatory decision making. Three endothelin receptor antagonists were investigated by developing target-mediated drug disposition (TMDD) PKPD models, explaining the nonlinear PK behaviour, hypothesising a class effect and revealing an effect on PK through endogenous rhythms in receptor fluctuation. The DDI potential of fluvoxamine is a therapeutically unpleasant characteristic, but useful for its usage as a lead substance for DDI predictions with physiology-based (PB) PK modelling. Fluvoxamine was investigated using a population PK approach, enabling the characterisation and quantification of the influence of CYP2D6 phenotype and cigarette smoking its PK, thus supporting the role of fluvoxamine in a network for DDI.Modellierungs- und Simulationstechniken (M&S) können zur Charakterisierung und zum Verständnis des pharmakokinetischen (PK) und pharmakodynamischen (PD) Verhaltens eines Arzneimittels eingesetzt werden und damit Dosierungsstrategien und Entscheidungsfindung während der Arzneimittelentwicklung und für regulatorische Zwecke unterstützen. Endothelin-Rezeptor-Antagonisten (ERAs) sind eine Klasse von kleinen Molekülen, die endogenes Endothelin- 1 (ET-1) von seinen Rezeptor-Bindungsstellen verdrängen. Da ET-1 in der Pathogenese verschiedener Erkrankungen eine Rolle spielt, sind ERAs interessante Verbindungen für die Behandlung von Erkrankungen, in denen das ET-1-System involviert ist. Bosentan war der erste ERA, der für die Behandlung der pulmonalen arteriellen Hypertonie (PAH), einer tödlichen und seltenen Krankheit, zugelassen wurde. Da Bosentan eine ausgeprägte nichtlineare PK und Variabilität in der PK und PD aufweist, wurde ein Populationsmodell entwickelt, um die Eigenschaften des Medikaments besser zu charakterisieren und zu verstehen. Ein sogenanntes target-mediated drug disposition (TMDD) PKPD-Modell beschrieb die nichtlineare PK von Bosentan am besten. So gelang es, die starke Rezeptor-Bindungsaffinität von Bosentan abzubilden und gleichzeitig die Verdrängung des natürlichen ET-1 aus diesen Bindungsstellen, sowie die Wirkung auf Blutdruck und Herzfrequenz zu beschreiben. Die für Bosentan entwickelte Modellstruktur, das TMDD-Modell, wurde erfolgreich auf dessen Nachfolgeprodukte Clazosentan und Tezosentan angewandt. Das Modell ermöglichte die Unterscheidung zwischen selektiven ETA- und nicht-selektiven ETA- / ETB-Rezeptorantagonisten, was sich in der fehlenden Internalisierung des Wirkstoff-Rezeptor-Komplexes für Clazosentan widerspiegelt. Darüber hinaus wurde eine zeitlich schwankende Rezeptorexpression in das Modell integriert, die das beobachtete Phänomen mehrfacher Spitzen in den Plasmakonzentrationen der PK Profile beschreiben kann. Zusätzliche wurde ein PK-Populationsmodell für Fluvoxamin entwickelt, um den Einfluß des CYP2D6- Phänotyps und des Rauchens auf die Clearance und die Fluvoxamin-Exposition zu untersuchen. Ein Ein- Kompartiment-Modell mit kombinierter linearer Absorption nullter und erster Ordnung sowie linearer Elimination wurde erfolgreich auf die Daten angewendet. Das Modell zeigte, dass bei schlechten CYP2C6 Metabolisierern höhere Fluvoxamin-Plasmakonzentrationen zu erwarten sind, da die Metabolisierung von Fluvoxamin durch CYP2D6 reduziert ist. Gleichzeitig wurde gezeigt, dass das Rauchen von Zigaretten den CYP1A2-Stoffwechsel von Fluvoxamin induziert und zusätzlich zu einer Abnahme der oralen Absorption führt. Folglich wird erwartet, dass die Exposition bei Rauchern im Vergleich zu Nichtrauchern abnimmt. Das Modell unterstrich und bestätigte die Ergebnisse eines physiologiebasierten PK (PBPK) Modells von Fluvoxamin als Teil eines Netzwerks für Arzneimittelwechselwirkungen mit Theophyllin, Koffein, Rifampicin und Midazolam, welches nun für Vorhersagen von Arzneimittelwechselwirkungen mit CYP1A2 verwendet werden kann

PHARMACOKINETIC AND PHARMCODYNAMIC STUDIES OF APOMORPHINE IN THE TREATMENT OF IDIOPATHIC PARKINSON'S DISEASE

There were two aspects to the study of apomorphine in the treatment of Parkinson' s disease: (i) a clinical pharmacokinetic-pharmacodynamic (PK-PD) study was designed and implemented in response to the challenges of apomorphine dose-titration in Parkinson's disease, and in view of the scarcity of available literature on the PK-PD relationships of apomorphine in Parkinson's disease, (ii) the PK(and tolerability)of apomorphine dosing using novel delivery/formulation combinations were explored in view of the inherent limitations associated with the conventional (ie. subcutaneous) route of administration of apomorphine (e.g. cutaneous nodule formation, needle-phobia). An HPLC assay was developed for the quantification of apomorphine in plasma, and stability issues relating to sample storage and assay were investigated. With regards to the first aspect of the research, simultaneous PK-PD modelling was performed, using an effect compartment model to account for counterclockwise hysteresis in a sub-group of patients. According to the traditional two-stage approach to data analysis, mean (standard deviation) clearance following subcutaneous bolus was 2.2 (0.5) L/kg/h, (apparent) volume of distribution was 1.9 (0.8) L/kg, absorption half-life was 4.1 (2.1) minutes and elimination half-life was 69.5 (21.1)minutes (n=7). Equilibration half-life was estimated for two patients at 8.3 and 16.5 minutes. Focus was given to investigating the relevance of a potential correlation (which had previously been identified using in-house pilot data) between post-distributional apomorphine PK and apomorphine-induced anti-parkinsonian response in patients with Parkinson's disease. It was hypothesised that this particular correlation may be of use in a dose-optimisation scheme. However it was demonstrated that, in the patients studied, the concept could not be applied to apomorphine dose-optimisation. The novel delivery systems under scrutiny were: (i) Britaject® (Britannia Pharmaceuticals Ltd.) apomorphine formulation administered subcutaneously using a needle-free (jet) injector (J-TIP®, National Medical Products Inc.), (ii) an intranasal apomorphine powder formulation delivered using a turbospin insufflator (CDFS), and (iii) an apomorphine hydrogel co-polymer produced as a dosage-form for buccal delivery (Controlled Therapeutics (Scotland) Ltd.). As a result of this work, a rationale for subsequent development of the novel systems was provided. Indeed, the needle-free and buccal systems were, in their existing format, shown not to convey a net advantage over the existing system. However the intranasal formulation, with a mean (standard deviation) relative bioavailability of 41 (18)% (n=16) compared to subcutaneous bolus administration (and with a favourable outcome as regards to tolerability), was considered to be potentially suitable for further development

Population pharmacokinetic modelling for dose optimization of esomeprazole to treat early-onset preeclampsia

Rationale Esomeprazole is a proton pump inhibitor with preclinical efficacy data showing it lowers concentrations of soluble fms like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), pathognomonic biomarkers identified in preeclampsia. A randomized controlled trial, Preeclampsia Intervention with Esomeprazole (PIE) trial, was conducted in South African women diagnosed with early-onset preeclampsia to investigate efficacy, but it found no change in clinical outcome or biomarker concentrations. It was hypothesized that the 40 mg daily oral dose was not enough to achieve therapeutic exposure. This study investigated the pharmacokinetics of esomeprazole in patients with early- onset preeclampsia with the aim to optimize the dose for future clinical trials. Methods Pharmacokinetic data from ten pregnant patients with early-onset preeclampsia from the PIE trial, median (range) age 30 (21-43) years, weight 98.8 (56-126) kg, and gestational age 29 (26- 31) weeks, were included for model development. In addition, pharmacokinetic data from non- pregnant healthy volunteers consisted of a pooled dataset of 26 male and female subjects, median (range) age of 21 (18-27) years and weight 69 (54-89) kg, who received 40 mg esomeprazole daily. Analysis of the pharmacokinetic data in pregnant patients was performed using nonlinear mixed-effects modelling with allometric scaling on clearance (CL) and volume of distribution (Vd). Metabolite to parent area under the time-concentration curve (AUCsulf/AUCeso and AUChyd/AUCeso) ratios were compared between pregnant and non-pregnant to assess metabolic changes in pregnancy. Simulations were performed with the model to determine the nonlinear increase in AUC with higher doses and with repeated dosing in the pregnant patients. Simulation results were compared with the preclinical target unbound concentration (0.917 mg/L) and preclinical target unbound AUC0-24 (9.29 mg·h/L). Results A one compartment pharmacokinetic model with first-order elimination and transit compartment absorption best described the data. Model estimated apparent CL and apparent Vd (95% CI) were 19.2 (14.2-26) L/h and 44.2 (29.9-56.6) L, respectively. Median AUCsulf/AUCeso (IQR) for pregnant patients, 2.00 (1.35-2.61) , was significantly higher than that for non-pregnant subjects on day1, 0.700 (0.636-1.00) , and day5, 1.18 (0.981- 1.58) . Median AUChyd/AUCeso (IQR) for pregnant patients, 0.0543 (0.0500-0.0914) , was not significantly different from that of non-pregnant subjects on day5, 0.0777 (0.0569-0.108) but lower than that of non-pregnant subjects on day1, 0.188 (0.156- 0.227). Simulation results showed that predicted steady state unbound Cmax is between 0.0949 and 0.398 mg/L while the predicted unbound AUC0-24 in pregnant patients with the highest dose of esomeprazole used clinically, i.e.120 mg BID, is between 0.696 and 2.92 mg·h/L. Discussion/Conclusion Model estimated CL/F and Vd/F are higher than values previously reported by other population pharmacokinetic models. AUCm/AUCp comparisons showed that esomeprazole metabolism in pregnancy appears to have shifted to the CYP3A4 pathway. This means that the nonlinear AUC increase expected with dose escalation and with repeated dosing are not as significant as in nonpregnant. Simulations indicate that pregnant patients are unlikely to achieve the target concentration and exposure with the highest dose of esomeprazole registered. Further research is necessary to determine the target site of action of esomeprazole in preeclampsia, and the pharmacokinetic metric that correlates with efficacy

An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as 'bath salts'

Material and methods. Methylone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (15 and 30 mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results. Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model with distribution and terminal elimination phases of α = 1.95 h− 1 and β = 0.72 h− 1. For oral administration, peak methylone concentrations were achieved between 0.5 and 1 h and fitted to a flip-flop model. Absolute bioavailability was about 80% and the percentage of methylone protein binding was of 30%. A relationship between methylone brain levels and free plasma concentration yielded a ratio of 1.42 ± 0.06, indicating access to the central nervous system. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate. Discussion. Pharmacokinetic and pharmacodynamic analysis of methylone showed a correlation between plasma concentrations and enhancement of the locomotor activity. A contribution of metabolites in the activity of methylone after oral administration is suggested. Present results will be helpful to understand the time course of the effects of this drug of abuse in humans

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours

Purpose: We have shown previously that carbogen (95% 02, 5% CO2) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. Methods: Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy (19F-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using 31P-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. Results: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of ∼60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, 19F-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and 31P-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, 19F-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly (p=0.0003) increased 5FU elimination from the tumour (i.e. decreased the t1/2) and significantly (p=0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. 31P-MRS showed there were significant (p≤0.02) increases in the hepatoma NTP/Pi ratio of 49% and transmembrane pH gradient of 0.11 units. Conclusions: We suggest that carbogen can transiently increase tumour blood flow, but this effect alone may not increase uptake of anticancer drugs without a secondary mechanism operating. In the case of the hepatoma, the increase in tumour energy status and pH gradient may be sufficient to augment 5FU metabolism to cytotoxic FNuct, while in the GH3 xenografts this was not the case. Thus carbogen breathing does not universally lead to increased uptake of anticancer drug

Population pharmacokinetics of dexamethasone in critically ill COVID-19 patients:Does inflammation play a role?

Purpose: The aim of this study is to design a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill COVID-19 patients in order to identify relevant covariates that can be used to personalize dosing regimens. Methods: Blood samples from critically ill patients receiving fixed-dose intravenous dexamethasone (6 mg/day) for the treatment of COVID-19 were sampled in a retrospective pilot study. The data were analyzed using Nonlinear Mixed Effects Modeling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated. Results: A total of 51 dexamethasone samples from 18 patients were analyzed and a two-compartment model fit the data best. The mean population estimates were 2.85 L/h (inter-individual-variability 62.9%) for clearance, 15.4 L for the central volume of distribution, 12.3 L for the peripheral volume of distribution and 2.1 L/h for the inter-compartmental distribution clearance. The covariate analysis showed a significant negative correlation between dexamethasone clearance and CRP. Conclusions: Dexamethasone PK parameters in ICU COVID patients were substantially different from those from non-ICU non-COVID patients, and inflammation may play an important role in dexamethasone exposure. This finding suggests that fixed-dose dexamethasone over several days may not be appropriate for ICU COVID patients.</p