Prediction of Minocycline Activity in the Gut From a Pig Preclinical Model Using a Pharmacokinetic -Pharmacodynamic Approach.
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SUBMITTER: Valle Q
PROVIDER: S-EPMC8299485 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development. Methods:In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure-response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug's potency (EC50) by the combining drug(s). Results:All combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity. Conclusions:With the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens.
| S-EPMC5890720 | biostudies-literature
Project description:The efficacy of HIV pre-exposure prophylaxis (PrEP) relies on adherence and may also depend on the route of HIV acquisition. Clinical studies of systemic tenofovir disoproxil fumarate (TDF) PrEP revealed reduced efficacy in women compared to men with similar degrees of adherence. To select the most effective PrEP strategies, preclinical studies are critically needed to establish correlations between drug concentrations (pharmacokinetics [PK]) and protective efficacy (pharmacodynamics [PD]). We utilized an in vivo preclinical model to perform a PK-PD analysis of systemic TDF PrEP for vaginal HIV acquisition. TDF PrEP prevented vaginal HIV acquisition in a dose-dependent manner. PK-PD modeling of tenofovir (TFV) in plasma, female reproductive tract tissue, cervicovaginal lavage fluid and its intracellular metabolite (TFV diphosphate) revealed that TDF PrEP efficacy was best described by plasma TFV levels. When administered at 50 mg/kg, TDF achieved plasma TFV concentrations (370 ng/ml) that closely mimicked those observed in humans and demonstrated the same risk reduction (70%) previously attained in women with high adherence. This PK-PD model mimics the human condition and can be applied to other PrEP approaches and routes of HIV acquisition, accelerating clinical implementation of the most efficacious PrEP strategies.
| S-EPMC5286499 | biostudies-literature
Project description:IntroductionCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR.ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.
| S-EPMC6754336 | biostudies-literature
Project description:ObjectiveCannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam.MethodsWe examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing ?-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together.ResultsCBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation.SignificanceOur study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.
| S-EPMC6900043 | biostudies-literature
Project description:Mathematical models are routinely used in clinical pharmacology to study the pharmacokinetic and pharmacodynamic properties of a drug in the body. Identifiability of these models is an important requirement for the success of these clinical studies. Identifiability is classified into two types, structural identifiability related to the structure of the mathematical model and deterministic identifiability which is related to the study design. There are existing approaches for assessment of structural identifiability of fixed-effects models, although their use appears uncommon in the literature. In this study, we develop an informal unified approach for simultaneous assessment of structural and deterministic identifiability for fixed and mixed-effects pharmacokinetic or pharmacokinetic-pharmacodynamic models. This approach uses an information theoretic framework. The method is applied both to simple examples to explore known identifiability properties and to a more complex example to illustrate its utility.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e49; doi:10.1038/psp.2013.25; advance online publication 19 June 2013.
| S-EPMC3697038 | biostudies-literature
Project description:Abstract Introduction Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The anti‐seizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease Preclinical Testing Core. Methods A multi‐tier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Results Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC0‐∞, and CL/F, and a dose dependence in AUC0‐∞. After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer 18F‐AV45, and 18F‐fluorodeoxyglucose (18F‐FDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drug‐ and dose‐related changes in gene expression relevant to human brain regions and pathways congruent with changes in 18F‐FDG uptake. Discussion This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted non‐linear kinetics based on dose and sex. Plasma concentrations of the 10 mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56 mg/kg doses were reflective of doses used to treat seizure activity. Post‐treatment gene expression analysis demonstrated LEV dose‐related changes in immune function and neuronal‐signaling pathways relevant to human AD, and aligned with regional 18F‐FDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Highlights Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice. Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic. Drug‐ and dose‐related differences in gene expression relevant to human brain regions and pathways were also similar to brain region–specific changes in 18F‐fluorodeoxyglucose uptake.
| S-EPMC9398229 | biostudies-literature
Project description:Frequently, we encounter the phenomenon of hysteresis in kinetic-dynamic modeling. The hysteresis loop in the concentration-effect curve suggests a time discrepancy caused by various pharmacokinetic and pharmacodynamic factors. To collapse the hysteresis loop and to simplify the concentration-effect relationship, several kinetic-dynamic modeling approaches including the effect compartment link model, turnover model (indirect response model), and tolerance/rebound model, have been used. The semicompartmental model is one method to describe the hysteresis of the pharmacokinetic-pharmacodynamic relationship. Furthermore, this semi-compartmental model differs from other models (full parametric approaches) as it does not require pharmacokinetic parameters to estimate pharmacodynamic parameters and ke0 . Therefore, we could employ a semi-compartmental approach in case it is difficult to apply the compartment model to pharmacokinetic data, as required for the pharmacodynamic analysis of inhalational anesthetics.
| S-EPMC7713860 | biostudies-literature
Project description:Histone deacetylase (HDAC) enzymatic activity has been linked to the transcription of DNA in cancers including multiple myeloma (MM). Therefore, HDAC inhibitors used alone and in combination are being actively studied as novel therapies in MM. In the present study, we investigated the preclinical activity of ACY-1215, an HDAC6-selective inhibitor, alone and in combination with bortezomib in MM. Low doses of ACY-1215 combined with bortezomib triggered synergistic anti-MM activity, resulting in protracted endoplasmic reticulum stress and apoptosis via activation of caspase-3, caspase-8, and caspase-9 and poly (ADP) ribosome polymerase. In vivo, the anti-MM activity of ACY-1215 in combination with bortezomib was confirmed using 2 different xenograft SCID mouse models: human MM injected subcutaneously (the plasmacytoma model) and luciferase-expressing human MM injected intravenously (the disseminated MM model). Tumor growth was significantly delayed and overall survival was significantly prolonged in animals treated with the combination therapy. Pharmacokinetic data showed peak plasma levels of ACY-1215 at 4 hours after treatment coincident with an increase in acetylated ?-tubulin, a marker of HDAC6 inhibition, by immunohistochemistry and Western blot analysis. These studies provide preclinical rationale for acetylated ?-tubulin use as a pharmacodynamic biomarker in future clinical trials.
| S-EPMC3337713 | biostudies-literature
Project description:The growing number of infections caused by multidrug-resistant pathogens has prompted a more rational use of available antibiotics given the paucity of new, effective agents. Monte Carlo simulations were utilized to determine the appropriateness of several doripenem dosing regimens based on the probability of attaining the critical drug exposure metric of time that drug concentrations remain above the drug MIC (T>MIC) for 35% (and lower thresholds) of the dosing interval in >80 to 90% of the population (T>MIC 35% target). This exposure level generally correlates with in vivo efficacy for carbapenems. In patients with creatinine clearance of >50 ml/min, a 500-mg dose of doripenem infused over 1 h every 8 h is expected to be effective against bacilli with doripenem MICs of < or =1 microg/ml based on a T>MIC 35% target and MICs of < or =2 microg/ml based on lower targets. A longer, 4-hour infusion time improved target attainment in most cases, such that the T>MIC was adequate for pathogens with doripenem MICs as high as 4 microg/ml. Efficacy is expected for infections caused by pathogens with doripenem MICs of < or =2 microg/ml in patients with moderate renal impairment (creatinine clearance, 30 to 50 ml/min) who receive doripenem at 250 mg infused over 1 h every 8 h and in patients with severe impairment (creatinine clearance between 10 and 29 ml/min) who receive doripenem at 250 mg, infused over 1 h or 4 h, every 12 h. Results of pharmacokinetics/pharmacodynamics (PK/PD) modeling can guide dose optimization, thereby potentially increasing the clinical efficacy of doripenem against serious Gram-negative bacterial infections.
| S-EPMC2876367 | biostudies-other
Project description:Mycobacterium abscessus is responsible for difficult-to-treat chronic pulmonary infections in humans. Current regimens, including parenteral administrations of cefoxitin (FOX) in combination with amikacin and clarithromycin, raise compliance problems and are frequently associated with high failure and development of resistance. Aerosol delivery of FOX could be an interesting alternative. FOX was administered to healthy rats by intravenous bolus or intratracheal nebulization, and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. After intrapulmonary administration, the FOX area under the curve within ELF was 1,147 times higher than that in plasma, indicating that this route of administration offers a biopharmaceutical advantage over intravenous administration. FOX antimicrobial activity was investigated using time-kill curves combined with a pharmacokinetic/pharmacodynamic (PK/PD) type modeling approach in order to account for its in vitro instability that precludes precise determination of MIC. Time-kill data were adequately described by a model including in vitro degradation, a sensitive (S) and a resistant (R) bacteria subpopulation, logistic growth, and a maximal inhibition-type growth inhibition effect of FOX. Median inhibitory concentrations were estimated at 16.2 and 252 mg/liter for the S and R subpopulations, respectively. These findings suggest that parenteral FOX dosing regimens used in patients for the treatment of M. abscessus are not sufficient to reduce the bacterial burden and that FOX nebulization offers a potential advantage that needs to be further investigated.
| S-EPMC6591628 | biostudies-literature