Drug Concentration-time Profiles Research Articles

Ertapenem's therapeutic potential for Mycobacterium avium lung disease in the hollow fibre model

IntroductionGuideline-based therapy for Mycobacterium avium complex (MAC) pulmonary disease achieves sustained sputum conversion rates in only 43–53% of patients. Repurposing of β-lactam antibiotics such as ertapenem could expedite design of more efficacious regimens, compared to developing new drugs. MethodsWe performed an ertapenem exposure-response study in the hollow fibre system model of intracellular MAC (HFS-MAC). We recapitulated human-like intrapulmonary concentration-time profiles of eight once-daily intravenous doses of ertapenem over 28 days and performed repetitive sampling for drug concentration-time profiles and MAC burden. The % of time concentration persisted above MIC (%TMIC) mediating either 50% or 80% of maximal effect (E50, EC80) were identified. The EC80 was used as target exposure in a 10 000 subject Monte Carlo experiments for ertapenem doses of 1G, 2G, or 4G administered once versus twice daily. ResultsThe ertapenem MIC ranged from 0.5 to 2 mg/L on three occasions. Ertapenem achieved a half-life of 4.04 ± 0.80 h in the HFS-MAC and killed a maximum of 2.17 log10 CFU/mL below day 0. The EC50 was %TMIC of 75.9% (95% confidence interval: 68.43%–86.54%) and the EC80 was %TMIC of 100%. Target attainment probability was >90% for 1G twice daily up to an MIC of 2 mg/L, while for 2G twice daily the susceptibility MIC breakpoint was 4–8 mg/L. ConclusionsErtapenem microbial kill below day 0 burden was better than guideline-based therapy drugs in the HFS-MAC in the past. Ertapenem is a promising drug for novel combination therapies for MAC lung disease.

Alleviating anxiety while breastfeeding: evaluating buspirone transfer into human milk.

Buspirone, an anxiolytic with minimal risk of dependence or respiratory depression, lacks extensive published data on its transfer into human milk during lactation. The objective of this study was to 1) quantify the transfer of buspirone and its active metabolite 1-pyrimidinylpiperazine (1-PP) into human milk, allowing for an estimation of maternal drug exposure to the breastfed infant, and 2) report observations of the infants exposed to buspirone via breastmilk. Milk samples and health histories were collected from nine lactating mothers who donated milk samples to the InfantRisk Human Milk Biorepository while taking buspirone. The drug concentration-time profile of buspirone and 1-PP was determined using liquid chromatography-mass spectrometry. Buspirone was below the detection level of 1.5ng/mL in all milk samples with dosages ranging from 7.5 to 30mg twice daily. However, low levels of active metabolite 1-PP were observed at 7.5mg twice daily up to 30mg twice daily. The relative infant dose (RID) calculated ranged from 0.21 to 2.17%, which is below the standard 10% threshold for infant safety. There were no reports of adverse effects in the exposed infants. The levels of buspirone observed in all participants' milk samples were exceedingly low. The subsequently low relative infant dose (RID) in the range of 0.21% to 2.17% is below the 10% threshold for infant safety, suggesting that the transfer of maternal buspirone and its active metabolite (1-PP) into human milk is clinically insignificant and poses minimal risk to a breastfed infant.

GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans.

Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability in the brain. A GastroPlus program was used to predict in vivo performance of immediate (IR) and sustained release (SR) products in humans. HSPiP software 5.4.08 predicted excipients with maximum possible miscibility of the drug. Based on the GastroPlus and HSPiP program, various excipients were screened for experimental solubility, nanoemulsions, and respective gel studies intended for nasal-to-brain delivery. These were characterized by size, size distribution, polydispersity index, zeta potential, morphology, pH, % transmittance, drug content, and viscosity. In vitro drug release, ex vivo permeation profile (goat nasal mucosa), and penetration studies were conducted. Results showed that in vivo oral drug dissolution and absorption were predicted as 98.6 mg and 18.8 mg, respectively, from both tablets (IR and SR) at 8 h using GastroPlus. The predicted drug access to the portal vein was substantially higher in IR (115 mg) compared to SR (82.6 mg). The plasma drug concentration-time profile predicted was in good agreement with published reports. The program predicted duodenum and jejunum as the prime sites of the drug absorption and no effect of nanonization on Tmax for sustained release formulation. Hansen parameters suggested a suitable selection of excipients. The program recommended nasal-to-brain delivery of the drug using a cationic mucoadhesive nanoemulsion. The optimized CVE6 was associated with the optimal size (113 nm), low PDI (polydispersity index) (0.26), high zeta potential (+34.7 mV), high transmittance (97.8%), and high strength (0.7% w/w). In vitro release and ex vivo permeation of CVE6 were found to be substantially high as compared to anionic AVE6 and respective gels. A penetration study using confocal laser scanning microscopy (CLSM) executed high fluorescence intensity with CVE6 and CVE6-gel as compared to suspension and ANE6. This might be attributed to the electrostatic interaction existing between the mucosal membrane and nanoglobules. Thus, cationic nanoemulsions and respective mucoadhesive gels are promising strategies for the delivery of VA to the brain through intransal administration for the treatment of seizures and convulsions.

Physiologically Based Pharmacokinetic Modeling of Bergamottin and 6,7-Dihydroxybergamottin to Describe CYP3A4 Mediated Grapefruit-Drug Interactions.

Grapefruit is a moderate to strong inactivator of CYP3A4, which metabolizes up to 50% of marketed drugs. The inhibitory effect is mainly attributed to furanocoumarins present in the fruit, irreversibly inhibiting preferably intestinal CYP3A4 as suicide inhibitors. Effects on CYP3A4 victim drugs can still be measured up to 24 hours after grapefruit juice (GFJ) consumption. The current study aimed to establish a physiologically-based pharmacokinetic (PBPK) grapefruit-drug interaction model by modeling the relevant CYP3A4 inhibiting ingredients of the fruit to simulate and predict the effect of GFJ consumption on plasma concentration-time profiles of various CYP3A4 victim drugs. The grapefruit model was developed in PK-Sim and coupled with previously developed PBPK models of CYP3A4 substrates that were publicly available and already evaluated for CYP3A4-mediated drug-drug interactions. Overall, 43 clinical studies were used for model development. Models of bergamottin (BGT) and 6,7-dihydroxybergamottin (DHB) as relevant active ingredients in GFJ were established. Both models include: (i) CYP3A4 inactivation informed by in vitro parameters, (ii) a CYP3A4 mediated clearance estimated during model development, as well as (iii) passive glomerular filtration. The final model successfully describes interactions of GFJ ingredients with 10 different CYP3A4 victim drugs, simulating the effect of the CYP3A4 inactivation on the victims' pharmacokinetics as well as their main metabolites. Furthermore, the model sufficiently captures the time-dependent effect of CYP3A4 inactivation as well as the effect of grapefruit ingestion on intestinal and hepatic CYP3A4 concentrations.

PBPK modeling of ivermectin-Considerations for the purpose of developing alternative routes to optimize its safety profile.

Although single-dose ivermectin has been widely used in mass-drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito-lethal effects at dosages greater and longer than those used to treat helminths. The final physiologically-based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration-time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6-30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg-p ontogenies), and pregnancy, especially if nonstandard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle-mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the body mass index of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administration. Administering lower doses over a longer period may attenuate the dependence on bile micelle-mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administration of ivermectin by complex generics in development.

Separate Evaluation of Fraction Absorbed and Intestinal Availability after Oral Administration of Drugs Based on the Measurement of Portal and Systemic Plasma Concentrations and Luminal Concentration.

There are several experimental methods to estimate the product of the fraction absorbed (Fa) and intestinal availability (Fg) in vivo after oral administration of drugs. Metabolic enzyme inhibitors are typically used to separate Fg from Fa·Fg. Since Fa·Fg can be regarded as Fa under metabolism-inhibited conditions, Fg can be isolated by dividing Fa·Fg by Fa. However, if the inhibition of intestinal metabolism is insufficient, Fa is overestimated, which results in an underestimation of Fg compared to the actual value. In this study, to avoid this problem, an experimental method for the separate estimation of Fa and Fg in rats without utilizing metabolic enzyme inhibitors was established. Buspirone, a CYP3A substrate, and ribavirin, a substrate of purine nucleoside phosphorylase and adenosine kinase, were selected as models. Following oral administration of the drugs with fluorescein isothiocyanate dextran 4000 (FD-4, an unabsorbable marker), Fa·Fg was pharmacokinetically calculated from portal and systemic plasma concentration-time profiles of model drugs and Fa was calculated from the difference in the ileal concentration profiles of the drugs and FD-4. Fg was evaluated by dividing Fa·Fg by Fa. Following oral administration, buspirone was not detected in any segment of the small intestine, indicating that the administered buspirone was completely absorbed. In addition, buspirone was extensively metabolized in enterocytes (Fg = 20.1). Ribavirin was primarily absorbed in the upper segment of the small intestine, and 64.4% of the ribavirin was absorbed before it reached the ileum. In addition, it was revealed that ribavirin was metabolized more extensively in the intestine than in the liver. Our method may be effective in quantitatively assessing Fa and Fg in vivo, which can help in the formulation design and prediction of drug-drug interactions.

Nanocrystallization Improves the Solubilization and Cytotoxic Effect of a Poly (ADP-Ribose)-Polymerase-I Inhibitor.

Olaparib (OLA) is an anticancer agent that acts by inhibiting the poly (ADP-ribose)-polymerase-I (PARP-I). Due to its low solubility and low permeability, it has been placed as a BCS Class-IV drug and hence its clinical use is limited. In this study, we develop the nanocrystals of OLA as a way to improve its solubility and other performances. The OLA-NCs were prepared by antisolvent precipitation method through homogenization and probe sonication technique using a novel amphiphilic polymeric stabilizer (Soluplus®). Particle characterization resulted approximately 103.13 nm, polydispersity-index was 0.104 with positive zeta-potential of +8.67 mV. The crystal morphology by SEM of OLA-NCs (with and without mannitol) exhibited nano-crystalline prism-like structures as compared to the elongated OLA-pure. The DSC, XRD and FTIR were performed to check the interaction of Soluplus, mannitol and OLA did not exhibit any physical interaction among the OLA, Soluplus® and mannitol that is indicated by the presence of parent wave number peak. Two-fold increased solubility of OLA was found in PBS with Soluplus® from the NCs (69.3 ± 6.2 µgmL-1) as compared to pure drug (35.6 ± 7.2 µgmL-1). In vitro release of drug from OLA-NCs was higher (78.2%) at 12 h at pH 6.8 and relatively lower (53.1%) at pH 1.2. In vitro cellular cytotoxicity and anticancer effects were examined on MCF-7 cells. OLA-NCs were found effectively potent to MCF-7 cells compared with OLA-pure with approximately less than half IC50 value during MTT assay. Estimation of p53, Caspase-3 and Caspase-9 in MCF-7 cells indicated that OLA-NCs have significantly (p < 0.05) increased their expressions. After single oral dose in rats, 12 h plasma drug concentration-time profile indicated approximately 2.06-, 2.29-, 2-25- and 2.62-folds increased Cmax, AUC0-12 h, AUC0-∞ and AUMC0-∞, respectively, from the NCs as compared to OLA-pure. Storage stability indicated that the OLA-NCs was physically and chemically stable at 4 °C, 25 °C and 40 °C up to 6-months. Overall, OLA-NCs were deliberated; its potential feasibility to overwhelm the formulation challenges related to poorly soluble drugs and its future clinical applications.

CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer.

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

Understanding the suitability of established antibiotics for oral inhalation from a pharmacokinetic perspective: an integrated model-based investigation based on rifampicin, ciprofloxacin and tigecycline in vivo data.

Treating pulmonary infections by administering drugs via oral inhalation represents an attractive alternative to usual routes of administration. However, the local concentrations after inhalation are typically not known and the presumed benefits are derived from experiences with drugs specifically optimized for inhaled administration. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to elucidate the pulmonary PK for ciprofloxacin, rifampicin and tigecycline and link it to bacterial PK/PD models. An exemplary sensitivity analysis was performed to potentially guide drug optimization regarding local efficacy for inhaled antibiotics. Detailed pulmonary tissue, endothelial lining fluid and systemic in vivo drug concentration-time profiles were simultaneously measured for all drugs in rats after intravenous infusion. Using this data, a PBPK/PD model was developed, translated to humans and adapted for inhalation. Simulations were performed comparing potential benefits of oral inhalation for treating bronchial infections, covering intracellular pathogens and bacteria residing in the bronchial epithelial lining fluid. The PBPK/PD model was able to describe pulmonary PK in rats. Often applied optimization parameters for orally inhaled drugs (e.g. high systemic clearance and low oral bioavailability) showed little influence on efficacy and instead mainly increased pulmonary selectivity. Instead, low permeability, a high epithelial efflux ratio and a pronounced post-antibiotic effect represented the most impactful parameters to suggest a benefit of inhalation over systemic administration for locally acting antibiotics. The present work might help to develop antibiotics for oral inhalation providing high pulmonary concentrations and fast onset of exposure coupled with lower systemic drug concentrations.

Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis. In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated. The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC. While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis.

Pharmacokinetics and bioequivalence of generic etoricoxib in healthy volunteers

Introduction/Study Objectives: A bioequivalence study was performed to compare the pharmacological profile of innovator etoricoxib (ETO) with a newly developed generic ETO, both in a 120 mg tablet formulation. A dissolution study was conducted to optimize the formulation process before evaluating physical changes in the active pharmaceutical ingredient and the formulated product. Methods: This was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover, truncated bioequivalence study involving a washout period of ten days. A total of 26 healthy male volunteers were recruited. The pharmacokinetic profile of the test formulation was compared with the reference formulation. Results/Discussion: The pharmacokinetic parameters of ETO were calculated based on the plasma drug concentration-time profile using non-compartmental analysis to determine its safety profile and tolerability. The Test/Reference (T/R) ratio of ETO was 104.36% (90% confidence interval (CI): 98.30%–110.80%) for area under curve (AUC)0-72 while the T/R ratio of maximum concentration (Cmax) was 101.39% (92.15%–111.56%). The 90% CI of the Cmax and AUC0-72 of ETO were within acceptable bioequivalence limits of 80%–125%. All values were within the predetermined limits of the Association of Southeast Asian Nation (ASEAN) bioequivalence guidelines. Conclusion: The test formulation was found to be bioequivalent with respect to the reference drug, according to ASEAN bioequivalence guidelines.

REGN1908-1909 monoclonal antibodies block Fel d 1 in cat allergic subjects: Translational pharmacokinetics and pharmacodynamics.

REGN1908‐1909, a 1:1 cocktail of two fully human IgG4 monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908‐1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration‐time profiles in serum for ascending doses of REGN1908‐1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (Cmax) and exposure increased proportionately with dose, with similar time to maximum concentration (Tmax) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half‐life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose‐limiting toxicities. REGN1908‐1909 is characterized by linear and dose‐proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8–12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof‐of‐mechanism study.

Pharmacokinetics and Bioequivalence Study of a New Branded Generic Moxifloxacin Tablet Among Healthy Volunteers.

A newly developed branded generic of a moxifloxacin (MOX) 400-mg tablet formulation was manufactured prior to this study. A bioequivalence (BE) study was done to assess the pharmacokinetics of the formulation using a randomized, open-label, 2-period crossover, 2-sequence, and single-dose experiment. Thirty healthy male volunteers were recruited. The test formulation, Flonoxin 400 mg, was compared with the reference formulation, Avelox 400 mg. The pharmacokinetic parameters of MOX were calculated based on the plasma drug concentration-time profile. Noncompartmental analysis was performed to determine its safety and tolerability. The 90% confidence intervals (CIs) were 88.5%-104.6%, 96.1%-101.1%, and 96.8%-100.7% for Cmax , AUC0-t , and AUC0-inf , respectively. All CIs were within the 80.0%-125.0% boundary, thus fulfilling the acceptable BE criteria according to the ASEAN guidelines.

Comparative Clinical Pharmacokinetics and Pharmacodynamics of Investigational Once-Daily Sustained-Release (SR) Vildagliptin 100 mg Tablet Formulation with Conventional 50 mg Twice-Daily Regimen in Healthy Indian Males

Background- Among the gliptins, vildagliptin is the only therapy requiring twice-daily dosing and thus adversely impacts patient adherence. To reduce dosing frequency, we developed a once-daily sustained-release (SR) vildagliptin 100 mg tablet formulation with potential to furnish comparable dipeptidyl peptidase-4 (DPP-4) inhibition coverage to the conventional twice-daily regimen. Objective- The current study compares the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of investigational once-daily SR vildagliptin 100 mg tablet formulation with the twice-daily dosage of marketed product, Galvus® in healthy Indian adult males after single and multiple-dose administration. Methods- Single and multiple-dose PK-PD assessment was conducted in separate clinical studies enrolling thirty-six healthy subjects under fed-condition. Each study was a randomized, open-label, two treatment, two-period, crossover design. Drug plasma concentrations were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. DPP-4 inhibition was estimated in the fluorescence-based assay. PK parameters were calculated from the plasma concentration-time curve employing Phoenix® WinNonlin® software. Formulation safety was evaluated by monitoring adverse events. Results- SR vildagliptin 100 mg tablet resulted in peak-less, nearly steady drug concentration-time profile. Thus, its mean PK characteristics after single [Cmax (147.7), AUC(0-24) (1645.04), Tmax (5.29 hr), t1/2 (4.61 hr)] and multiple-dose [Cmaxss (163.59), AUCss (0-24) (1815.36), and Tmaxss (4.65 hrs), t1/2ss (3.71 hr)] administrations were significantly distinct from the Galvus® twice-daily regimen. SR vildagliptin 100 mg tablet demonstrated more than 80% DPP-4 inhibition profile for approximately 23 hrs in both the studies which was comparable to Galvus® twice-daily regimen. Conclusions- Investigational SR vildagliptin 100 mg tablet formulation was found to be safe and well-tolerated. Its ability to provide nearly 80% DPP-4 inhibition coverage over 23 hrs post-dose may reduce the additional pill burden in patients on conventional twice-daily regimen.

An UPLC-MS/MS method to monitor Estriol injection and comparison of pharmacokinetic characteristics after irradiation

ObjectiveTo develop an UPLC-MS/MS method for the accurate quantification of Estriol (E3), a new radioprotective agent, and observe the variation in pharmacokinetic characteristics of E3 after irradiation. As a hormone drug, the gender differences of E3 metabolism were also concerned here. MethodsVarious chromatographic and mass spectrometric conditions of E3 were optimized. The specificity, linearity, precision and accuracy of UPLC-MS/MS method were validated. Twenty SD rats, half male and half female, were administered with intramuscular (im) injection of 2.7 ​mg/kg E3, and then divided randomly into two groups, sham-irradiated group (Con) and irradiated group (IR). IR group was irradiated to 7 ​Gy of γ-rays. Blood samples were collected at different times post-irradiation and E3 concentrations were detected. The changes of concentration-time variation and pharmacokinetic parameters for E3 after irradiation were investigated, together with metabolic differences between male and female rats. ResultsThe range of the calibration curve of UPLC-MS/MS for E3 was 1.00–200.0 ​ng/mL. Con group reached maximum concentration (Cmax) (77.57 ​± ​18.71) ng/mL at (0.68 ​± ​0.29) h (Tmax) after im injection. The drug concentration-time profiles and pharmacokinetic parameters of E3 were consistent before and after irradiation. The areas under time curve (AUC0-t) of E3 were (353 ​± ​74) h·ng/mL for Con group, and (299 ​± ​74) h·ng/mL for IR group (P ​> ​0.05). There were also no statistical differences in pharmacokinetic parameters between female and male rats. The elimination half-lifes (T1/2) of males and females were (3.02 ​± ​0.68) h and (3.01 ​± ​0.42) h in Con group, and (3.64 ​± ​0.51) h and (3.38 ​± ​0.60) h in IR group, respectively (P ​> ​0.05). ConclusionA rapid and sensitive UPLC-MS/MS method for determination of E3 was established. The pharmacokinetic characteristics of E3 in rat were not affected by 7 ​Gy irradiation and gender differences. This study provided a theoretical basis for the development and application of new radiation injury treatment drug.

Successful Prediction of Human Steady-State Unbound Brain-to-Plasma Concentration Ratio of P-gp Substrates Using the Proteomics-Informed Relative Expression Factor Approach.

In order to optimize central nervous system (CNS) drug development, accurate prediction of the drug’s human steady‐state unbound brain interstitial fluid‐to‐plasma concentration ratio (Kp,uu,brain) is critical, especially for drugs that are effluxed by the multiple drug resistance transporters (e.g., P‐glycoprotein, P‐gp). Due to lack of good in vitro human blood‐brain barrier models, we and others have advocated the use of a proteomics‐informed relative expressive factor (REF) approach to predict Kp,uu,brain. Therefore, we tested the success of this approach in humans, with a focus on P‐gp substrates, using brain positron emission tomography imaging data for verification. To do so, the efflux ratio (ER) of verapamil, N‐desmethyl loperamide, and metoclopramide was determined in human P‐gp‐transfected MDCKII cells using the Transwell assay. Then, using the ER estimate, Kp,uu,brain of the drug was predicted using REF (ER approach). Alternatively, in vitro passive and P‐gp–mediated intrinsic clearances (CLs) of these drugs, estimated using a five‐compartmental model, were extrapolated to in vivo using REF (active CL) and brain microvascular endothelial cells protein content (passive CL). The ER approach successfully predicted Kp,uu,brain of all three drugs within twofold of observed data and within 95% confidence interval of the observed data for verapamil and N‐desmethyl loperamide. Using the in vitro–to–in vivo extrapolated clearance approach, Kp,uu,brain was reasonably well predicted but not the brain unbound interstitial fluid drug concentration‐time profile. Therefore, we propose that the ER approach be used to predict Kp,uu,brain of CNS candidate drugs to enhance their success in development.

A 3D brain unit model to further improve prediction of local drug distribution within the brain.

The development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF). Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and transcellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed. In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.

Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions.

For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration–time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.

Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber In Vitro Infection Model.

Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 106 CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 108 CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections.

Transfer of Dicloxacillin into Human Milk

Background: Dicloxacillin is a beta-lactam antibiotic that is commonly used in the treatment of lactational mastitis in breastfeeding women. Although penicillins have long been considered safe for breastfeeding mothers and their infants, there is almost no data on the transfer of dicloxacillin into human breast milk despite the fact that it is commonly used for mastitis. Case Report: This study determined the drug concentration-time profile of dicloxacillin in milk samples collected from three lactating mothers consuming 500 mg dicloxacillin taken every 6 hours for treatment of mastitis. Milk levels were measured using liquid chromatography mass spectrometry. The maximum concentration of dicloxacillin in milk was 67.6 ng/mL. The relative infant dose (RID) was calculated to be 0.03%. This value is well below the theoretical level of concern of 10%. Discussion: The limited transfer of dicloxacillin into human milk is probably explained by the high plasma protein binding of dicloxacillin and its subsequent poor penetration into human milk. Conclusion: In this case series, the level of dicloxacillin in milk was found to be very low, and the RID to be only 0.03% of the maternal dose. Although the levels detected were low, dicloxacillin does transfer into breast milk. Caution should be exercised in infants with hypersensitivity to penicillins.