Lactic acidosis after allogeneic haematopoietic stem cell transplantation potentially related to letermovir.

A 53-year-old woman with a history of acute myeloid leukaemia received a second allogeneic haematopoietic stem cell transplant and was prescribed, among other medications, acyclovir and letermovir (480-mg daily oral dose) for prophylaxis of, respectively, herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit for dyspnoea and oliguria. Laboratory investigations revealed acute kidney injury but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma raised the suspicion of mitochondrial toxicity. Letermovir therapy was interrupted, and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (38.7 h) that was not significantly influenced by continuous venovenous haemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted nonfunctional organic anion transporting polypeptide 1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

Pharmacokinetics, Safety, and Tolerability of Letermovir Following Single- and Multiple-Dose Administration in Healthy Japanese Subjects.

Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1-single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2-multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half-life of ≈10 to 13 hours. The post absorption plasma concentration-time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple-dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5- to 2.5-fold higher than that observed in non-Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.

Simultaneous determination of febuxostat and montelukast in human plasma using fabric phase sorptive extraction and high performance liquid chromatography-fluorimetric detection.

In the present work, a new sensitive and selective high-performance liquid chromatography-fluorimetric detection (HPLC-FLD) method was developed and validated to quantify febuxostat (FBX) and montelukast (MON) in human plasma. The developed procedure was successfully applied to a study aimed at evaluating the pharmacokinetic profiles of febuxostat and montelukast in human plasma. A sol-gel poly (caprolactone)-block-poly(dimethylsiloxane)-block-poly(caprolactone) (sol-gel PCAP-PDMS-PCAP) extraction sorbent coated fabric phase sorptive extraction membrane was used in the extraction process. The entire chromatographic analysis was performed with isocratic elution of the composition of the mobile phase (acetonitrile:water, 60:40, v:v, 0.032% glacial acetic acid) on the C18 column. The flow rate is varied during the analysis, particularly from 0.5 mL min-1 at the start and linearly increased to 1.5 mL min-1 in 7 min. The detection and quantification of the analytes was carried out by means of a fluorimetric detector at 320 nm and 350 nm as absorption wavelengths and at 380 and 400 nm as emission wavelengths for FBX and MON, respectively. The calibration curves demonstrated linearity in the range 0.3-10 ng mL-1 and 5-100 ng mL-1 for FBX and MON, respectively, while the LOD and LOQ values were 0.1 and 0.3 ng mL-1 for FBX and 1.5 and 5 ng mL-1 for MON. Intraday and interday RSD% values were found lower than 5.79%. As reported, the method was applied to real plasma samples obtained from a volunteer who was co-administered both the drugs. Pharmacokinetic data reveal that the concentration of both the drugs reaches the plateau approximately at the same time, but exhibits an elimination phase at different rates. This study demonstrated the usefulness of the new method and its applicability in therapeutic drug monitoring (TDM).

Acute and Chronic Effects of Rifampin on Letermovir Suggest Transporter Inhibition and Induction Contribute to Letermovir Pharmacokinetics.

Rifampin has acute inhibitory and chronic inductive effects that can cause complex drug-drug interactions. Rifampin inhibits transporters including organic-anion-transporting polypeptide (OATP)1B and P-glycoprotein (P-gp), and induces enzymes and transporters including cytochrome P450 3A, UDP-glucuronosyltransferase (UGT)1A, and P-gp. This study aimed to separate inhibitory and inductive effects of rifampin on letermovir disposition and elimination (indicated for cytomegalovirus prophylaxis in hematopoietic stem cell transplant recipients). Letermovir is a substrate of UGT1A1/3, P-gp, and OATP1B, with its clearance primarily mediated by OATP1B. Letermovir (single-dose) administered with rifampin (single-dose) resulted in increased letermovir exposure through transporter inhibition. Chronic coadministration with rifampin (inhibition plus potential OATP1B induction) resulted in modestly decreased letermovir exposure vs. letermovir alone. Letermovir administered 24 hours after the last rifampin dose (potential OATP1B induction) resulted in markedly decreased letermovir exposure. These data suggest rifampin may induce transporters that clear letermovir; the modestly reduced letermovir exposure with chronic rifampin coadministration likely reflects the net effect of inhibition and induction. OATP1B endogenous biomarkers coproporphyrin (CP) I and glycochenodeoxycholic acid-sulfate (GCDCA-S) were also analyzed; their exposures increased after single-dose rifampin plus letermovir, consistent with OATP1B inhibition and prior reports of inhibition by rifampin alone. CP I and GCDCA-S exposures were substantially reduced with letermovir administered 24 hours after the last dose of rifampin vs. letermovir plus chronic rifampin coadministration. This study suggests that OATP1B induction may contribute to reduced letermovir exposure after chronic rifampin administration, although given the complexity of letermovir disposition alternative mechanisms are not fully excluded.

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.

Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles.

CONTEXT: As an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact. OBJECTIVE: The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles. MATERIALS AND METHODS: The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters. RESULTS: The assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5-91.58% and 94.98-99.67%, while for ACT-333679 were 81.21-93.90% and 93.17-99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in Cmax and AUC0-t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively. DISCUSSION AND CONCLUSION: The study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.

Development and Full Validation of a Bioanalytical Method for Quantifying Letermovir in Human Plasma Using Ultra-Performance Liquid Chromatography Coupled with Mass Spectrometry.

With the aim of studying the pharmacokinetics of letermovir, which is a newly developed antiviral agent for human cytomegalovirus, a rapid and simple ultra-performance liquid chromatography coupled with mass spectrometry (UPLC/MS) method was developed and validated for the quantification of letermovir in human plasma. Separation was performed in reverse phase mode using an ACQUITY UPLC BEH C18 column (130 Å, 1.7 µm, 2.1 × 50 mm) at a flow rate of 0.3 mL/min, 10 mM ammonium acetate-0.1% formic acid solution as mobile phase A, and acetonitrile as mobile phase B with a gradient elution. The method was validated over a linear range of 10-1000 ng/mL with a coefficient of determination (R2) >0.99 using weighted linear regression analysis. The intra- and inter-assay accuracy (nominal%) and precision (relative standard deviation%) were within ±15 and ≤15%, respectively. The specificity, recovery, matrix effect, stability, and dilution integrity of this method were also within acceptable limits. This method could be useful in studying the pharmacokinetics and pharmacodynamics, as well as performing the therapeutic drug monitoring of letermovir.

Case Study 5: Predicting the Drug Interaction Potential for Inhibition of CYP2C8 by Montelukast.

Predicting drug-drug interactions (DDIs) from in vitro data is made difficult by not knowing concentrations of substrate and inhibitor at the target site. For in vivo targets, this is understandable, since intracellular concentrations can differ from extracellular concentrations. More vexing is that the concentration of the drug at the target for some in vitro assays can also be unknown. This uncertainty has resulted in standard in vitro practices that cannot accurately predict human pharmacokinetics. This case study highlights the impact of drug distribution, both in vitro and in vivo, with the example of the drug interaction potential of montelukast.

Association between [68Ga]NODAGA-RGDyK uptake and dynamics of angiogenesis in a human cell-based 3D model.

Radiolabeled RGD peptides targeting expression of αvß3 integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [68Ga]NODAGA-RGDyK to αvß3 integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [68Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [68Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [68Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.

A New Workflow for Drug Metabolite Profiling by Utilizing Advanced Tribrid Mass Spectrometry and Data-Processing Techniques.

Drug metabolite profiling utilizes liquid chromatography with tandem mass spectrometry (LC/MS/MS) to acquire ample information for metabolite identification and structural elucidation. However, there are still challenges in detecting and characterizing all potential metabolites that can be masked by a high biological background, especially the unknown and uncommon ones. In this work, a novel metabolite profiling workflow was established on a platform using a state-of-the-art tribrid high-resolution mass spectrometry (HRMS) system. Primarily, an instrumental method was developed based on the novel design of the tribrid system that facilitates in-depth MSn scans with two fragmentation devices. Additionally, different advanced data acquisition techniques were assessed and compared, and automatic background exclusion and deep-scan approaches were adopted to promote assay efficiency and metabolite coverage. Finally, different data-analysis techniques were explored to fully extract metabolite data from the information-rich MS/MS data sets. Overall, a workflow combining tribrid mass spectrometry and advanced acquisition methodology has been developed for metabolite characterization in drug discovery and development. It maximizes the tribrid HRMS platform's utility and enhances the coverage, efficiency, quality, and speed of metabolite profiling assays.

Montelukast microsuspension with hypromellose for improved stability and oral absorption.

Oral montelukast (MTK) is prescribed to treat asthma or rhinitis, and is clinically investigated as new medication in the treatment of Alzheimer's dementia. Herein, in order to better patient's compliance, microsuspensions (MSs)-based oral liquid preparations of montelukast (MTK) were formulated with polymeric suspending agents including hypromellose (HPMC), and those drug-polymer interaction, physicochemical stability, dissolution, and in vivo pharmacokinetic profile was evaluated. When amorphous MTK particle was suspended in aqueous vehicle, it was readily converted into crystalline form and grown into aggregates, drastically lowering dissolution rate. However, the addition of HPMC polymer markedly suppressed the crystal growth, providing both improved drug stability and profound dissolution profile. Raman spectrometry denoted the inter-molecular hydrogen boding between MTK particle and HPMC polymer. The crystal growth or dissolution profile of MSs was markedly affected by pharmaceutical additives (sucrose or simethicone) in the preparations or storage temperature. The optimized HPMC-based MS exhibited over 80% higher bioavailability, compared to marketed granule (Singulair®) in rats. Therefore, novel MTK-loaded MS can be a promising liquid preparation, bettering oral absorption and patient's compliance.

Liposomes with Water as a pH-Responsive Functionality for Targeting of Acidic Tumor and Infection Sites.

A lipid named DCPA was synthesized under microwave-assisted heating. DCPA possesses a pyridine betaine, hydrophilic group that can be complexed with water through hydrogen bonding (DCPA-H2 O). DCPA-H2 O liposomes became protonated relatively fast already at pH<6.8, due to the high HOMO binding energy of DCPA-H2 O. In murine models, DCPA-H2 O liposomes had longer blood circulation times than natural DPPC or cationic DCPM liposomes, while after tail-vein injection DCPA-H2 O liposomes targeted faster to solid tumors and intra-abdominal infectious biofilms. Therapeutic efficacy in a murine, infected wound-healing model of tail-vein injected ciprofloxacin-loaded DCPA-H2 O liposomes exceeded the ones of clinically applied ciprofloxacin as well as of ciprofloxacin-loaded DPPC or DCPM liposomes.

Evaluation of glucagon-like peptide-1 receptor expression in nondiabetic and diabetic atherosclerotic mice using PET tracer 68Ga-NODAGA-exendin-4.

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.

Pharmacokinetics of 2-phenoxyethanol and its major metabolite, phenoxyacetic acid, after dermal and inhaled routes of exposure: application to development PBPK model in rats.

2-Phenoxyethanol (PE), ethylene glycol monophenyl ether, is widely used as a preservative in cosmetic products as well as in non-cosmetics. Since PE has been used in many types of products, it can be absorbed via dermal or inhaled route for systemic exposures. In this study, the pharmacokinetic (PK) studies of PE and its major metabolite, phenoxyacetic acid (PAA), after dermal (30 mg and 100 mg) and inhaled administration (77 mg) of PE in rats were performed. PE was administered daily for 4 days and blood samples were collected at day 1 and day 4 for PK analysis. PE was rapidly absorbed and extensively metabolized to form PAA. After multiple dosing, the exposures of PE and PAA were decreased presumably due to the induction of metabolizing enzymes of PE and PAA. In dermal mass balance study using [14C]-phenoxyethanol ([14C]PE) as a microtracer, most of the PE and its derivatives were excreted in urine (73.03%) and rarely found in feces (0.66%). Based on these PK results, a whole-body physiologically-based pharmacokinetic (PBPK) model of PE and PAA after dermal application and inhalation in rats was successfully developed. Most of parameters were obtained from the literatures and experiments, and intrinsic clearance at steady-state (CLint,ss) were optimized based on the observed multiple PK data. With the developed model, systemic exposures of PE and PAA after dermal application and inhalation were simulated following no-observed-adverse-effect level (NOAEL) of 500 mg/kg/day for dermal application and that of 12.7 mg/kg/day for inhalation provided by the Environmental Protection Agency. The area under the concentration-time curve at steady state (AUCss) in kidney and liver (and lung for inhalations), which are known target organs of exhibiting toxicity of PE, as well as AUCss in plasma of PE and PAA were obtained from the model.

In Vivo Molecular Imaging of the Efficacy of Aminopeptidase N (APN/CD13) Receptor Inhibitor Treatment on Experimental Tumors Using 68Ga-NODAGA-c(NGR) Peptide.

INTRODUCTION: The aminopeptidase N (APN/CD13) receptor plays an important role in the neoangiogenic process and metastatic tumor cell invasion. Clinical and preclinical studies reported that bestatin and actinonin are cytotoxic to APN/CD13-positive tumors and metastases due to their APN/CD13-specific inhibitor properties. Our previous studies have already shown that 68Ga-labeled NGR peptides bind specifically to APN/CD13 expressing tumor cells. The APN/CD13 specificity of 68Ga-NGR radiopharmaceuticals enables the following of the efficacy of antiangiogenic therapy with APN/CD13-specific inhibitors using positron emission tomography (PET). The aim of this in vivo study was to assess the antitumor effect of bestatin and actinonin treatment in subcutaneous transplanted HT1080 and B16-F10 tumor-bearing animal models using 68Ga-NODAGA-c(NGR). MATERIALS AND METHODS: Three days after the inoculation of HT1080 and B16-F10 cells, mice were treated with intraperitoneal injection of bestatin (15 mg/kg) or actinonin (5 mg/kg) for 7 days. On the 5th and 10th day, in vivo PET scans and ex vivo biodistribution studies were performed 90 min after intravenous injection of 5.5 ± 0.2 MBq68Ga-NODAGA-c(NGR). RESULTS: Control-untreated HT1080 and B16-F10 tumors were clearly visualized by the APN/CD13-specific 68Ga-NODAGA-c(NGR) radiopharmaceutical. The western blot analysis also confirmed the strong APN/CD13 positivity in the investigated tumors. We found significantly (p ≤ 0.05) lower radiopharmaceutical uptake after bestatin treatment and higher radiotracer accumulation in the actinonin-treated HT1080 tumors. In contrast, significantly lower (p ≤ 0.01) 68Ga-NODAGA-c(NGR) accumulation was observed in both bestatin- and actinonin-treated B16-F10 melanoma tumors compared to the untreated-control tumors. Bestatin inhibited tumor growth and 68Ga-NODAGA-c(NGR) uptake in both tumor models. CONCLUSION: The bestatin treatment is suitable for suppressing the neoangiogenic process and APN/CD13 expression of experimental HT1080 and B16-F10 tumors; furthermore, 68Ga-NODAGA-c(NGR) is an applicable radiotracer for the in vivo monitoring of the efficacy of the APN/CD13 inhibition-based anticancer therapies.

Pharmacokinetics and Bioequivalence Evaluation of Two Montelukast Sodium Chewable Tablets in Healthy Chinese Volunteers Under Fasted and Fed Conditions.

PURPOSE: The aim of this study was to assess and compare the pharmacokinetic (PK) properties and bioequivalence of montelukast sodium chewable tablets prepared by two different manufacturers in healthy Chinese volunteers to obtain adequate PK evidence for the registration approval of the test formulation. PATIENTS AND METHODS: A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR20182362). Eighteen subjects each were selected for a fasted study and a fed study. Eligible participants were randomly assigned in a 1:1 ratio to receive a single dose of the reference formulation or the test formulation, followed by a 5-day washout period and the administration of the alternate formulation. Plasma samples were collected over a 24-hour period following tablet administration and analyzed for montelukast contents by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The PK parameters, such as maximum serum concentration (Cmax), area under the curve (AUC) from t = 0 to the last quantifiable concentration (AUC0-t), AUC from t = 0 to infinity (AUC0-∞), half-life (t1/2), time to Cmax (Tmax), and terminal elimination rate constant (λz), were evaluated. The safety assessment included changes in vital signs (blood pressure, pulse, and temperature) or laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and the incidence of adverse events (AEs). RESULTS: The geometric mean ratios (GMRs) between the two formulations for the primary pharmacokinetic parameters (Cmax, AUC0-24, and AUC 0-∞) and the corresponding 90% confidence intervals (Cis) were all within the range of 80.00-125.00% for both the fasting and fed states. The safety profiles for both treatments were comparable. CONCLUSION: The PK analysis revealed that the test and reference formulations of montelukast sodium chewable tablets were bioequivalent and well-tolerated by healthy Chinese subjects.

Absorption, Metabolism, Distribution, and Excretion of Letermovir.

BACKGROUND: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients. OBJECTIVE: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters in vitro were investigated to inform on the potential for drug-drug interactions (DDIs). METHODS: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters was evaluated in vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment. RESULTS: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration- dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp. CONCLUSION: The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.

Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients.

Letermovir is indicated for prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Two-stage population pharmacokinetic (PK) modeling of letermovir was conducted to support dose rationale and evaluate the impact of intrinsic/extrinsic factors. Data from healthy phase I study participants over a wide dose range were modeled to evaluate the effects of selected intrinsic factors, including pharmacogenomics; next, phase III HSCT-recipient data at steady-state following clinical doses were modeled. The model in HSCT recipients adequately described letermovir PK following both oral or i.v. administration, and was consistent with the healthy participant model at steady-state clinical doses. Intrinsic factor effects were not clinically meaningful. These staged analyses indicate that letermovir PK in HSCT recipients and healthy participants differ only with respect to bioavailability and absorption rate. The HSCT recipient model was suitable for predicting exposure for exposure-response analysis supporting final dose selection.

A Review of Different Analytical Techniques for Fexofenadine Hydrochloride and Montelukast Sodium in Different Matrices.

Fexofenadine hydrochloride is an antihistamine agent used for the treatment of allergic disorders like rhinitis. It is a second generation antihistamine. Montelukast sodium is an anti-asthmatic agent and leukotriene receptor antagonist used in the treatment of respiratory disorders. This article exemplifies the reported analytical methods like electrometric methods, ultraviolet spectroscopy, mass spectroscopy, thin layer chromatography, high performance liquid chromatography, high performance thin layer chromatography and tandem spectroscopy for determination of fexofenadine HCl and montelukast sodium in dosage form and in biological matrices. This review covers almost all the analytical methods for fexofenadine hydrochloride and montelukast sodium form 1968-2018 years. Complete analytical validation parameters reported are discussed in this review for both analytes. Among various analytical methods, HPLC and UV-visible spectrophotometry were found to be the most extensively used methods by the researchers.

Assessment of Pharmacokinetic Interaction Between Letermovir and Fluconazole in Healthy Participants.

Letermovir is a prophylactic agent for cytomegalovirus infection and disease in adult cytomegalovirus-seropositive recipients of allogeneic hematopoietic stem cell transplant. As the antifungal agent fluconazole is administered frequently in transplant recipients, a drug-drug interaction study was conducted between oral letermovir and oral fluconazole. A phase 1 open-label, fixed-sequence study was performed in healthy females (N = 14, 19-55 years). In Period 1, a single dose of fluconazole 400 mg was administered. Following a 14-day washout, a single dose of letermovir 480 mg was administered (Period 2), and after a 7-day washout, single doses of fluconazole 400 mg and letermovir 480 mg were coadministered in Period 3. Pharmacokinetics and safety were evaluated. The pharmacokinetics of fluconazole and letermovir were not meaningfully changed following coadministration. Fluconazole geometric mean ratio (GMR; 90% confidence interval [CI]) with letermovir for area under the concentration-versus-time curve from time 0 to infinity (AUC0-∞ ) was 1.03 (0.99-1.08); maximum concentration (Cmax ) was 0.95 (0.92-0.99). Letermovir AUC0-∞ GMR (90%CI) was 1.11 (1.01-1.23), and Cmax was 1.06 (0.93-1.21) following coadministration with fluconazole. Coadministration of fluconazole and letermovir was generally well tolerated.