Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.

BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults.

AIMS: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. METHODS: Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. RESULTS: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. CONCLUSIONS: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants.

AIMS: To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate). METHODS: PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment. RESULTS: After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUCinf and Cmax , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUCinf and Cmax increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUCinf and Cmax . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran Cmax with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported. CONCLUSION: Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.

Patient Centric Microsampling to Support Paxlovid Clinical Development: Bridging and Implementation.

Nirmatrelvir is a potent and selective severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease inhibitor. Nirmatrelvir co-packaged with ritonavir (as PAXLOVID) received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) on December 22, 2021, as an oral treatment for coronavirus disease 2019 (COVID-19) and subsequent new drug application approval on May 25, 2023. Pharmacokinetic (PK) capillary blood sampling at-home using Tasso-M20 micro-volumetric sampling device was implemented in the program, including three phase II/III outpatient and several clinical pharmacology studies supporting the EUA. The at-home sampling complemented venous blood sampling procedures to enrich the PK dataset, to decrease the need for patients' site visit for PK sampling, and to allow different sampling approaches for flexibility and convenience. To demonstrate concordance/equivalence, bridging between venous plasma and Tasso dried blood results was conducted by comparing concentrations and derived PK parameters from both sampling approaches. In addition, a two-compartment population PK model was utilized to bridge the plasma and Tasso data by estimating the PK parameters using blood-to-plasma ratio as a slope parameter. Operational challenges were successfully managed to implement at-home PK sampling in global phase II/III trials. Sample quality was generally very good with less than 3% samples deemed as "not usable" from over 800 samples collected in all the studies. Experience gained from sites and patients will guide future broader implementations.

A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir.

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC90), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC90) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC90). Drug interactions with nirmatrelvir/ritonavir (PAXLOVIDTM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.

Pharmacokinetics of anidulafungin in critically ill patients with candidemia/invasive candidiasis.

The pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-year-old 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m(2), respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC(0-24)), maximum concentration (C(max)), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC(0-24) and Cmax in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.

Quantification of brain voriconazole levels in healthy adults using fluorine magnetic resonance spectroscopy.

Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the blood-brain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid, so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open-label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 h on day 1, followed by 200 mg every 12 h administered orally over a 3-day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the MIC for Aspergillus. The brain/plasma ratios were 3.0 at steady state on day 3 (predose) and 1.9 postdose. We found that voriconazole is able to penetrate the brain tissue, which can be quantified using a noninvasive MRS technique. (This study has been registered at ClinicalTrials.gov under registration no. NCT00300677.).

Real-World Evidence of the Top 100 Prescribed Drugs in the USA and Their Potential for Drug Interactions with Nirmatrelvir; Ritonavir.

Nirmatrelvir (coadministered with ritonavir as PAXLOVIDTM) reduces the risk of COVID-19-related hospitalizations and all-cause death in individuals with mild-to-moderate COVID-19 at high risk of progression to severe disease. Ritonavir is coadministered as a pharmacokinetic enhancer. However, ritonavir may cause drug-drug interactions (DDIs) due to its interactions with various drug-metabolizing enzymes and transporters, including cytochrome P450 (CYP) 3A, CYP2D6, and P-glycoprotein transporters. To better understand the extent of DDIs (or lack thereof) of nirmatrelvir; ritonavir in a clinical setting, this study used real-world evidence (RWE) from the Optum Clinformatics Data Mart database to identify the top 100 drugs most commonly prescribed to US patients at high risk of progression to severe COVID-19 disease. The top 100 drugs were identified based on total counts associated with drugs prescribed to high-risk patients (i.e., ≥ 1 medical condition associated with an increased risk of severe COVID-19) who were continuously enrolled in the database throughout 2019 and had ≥ 1 prescription claim. Each of the 100 drugs was then assessed for DDI risk based on their metabolism, excretion, and transport pathways identified from available US prescribing and medical literature sources. Seventy drugs identified were not expected to have DDIs with nirmatrelvir; ritonavir, including many cardiovascular agents, anti-infectives, antidiabetic agents, and antidepressants. Conversely, 30 drugs, including corticosteroids, narcotic analgesics, anticoagulants, statins, and sedatives/hypnotics, were expected to cause DDIs with nirmatrelvir; ritonavir. This RWE analysis is complementary to the prescribing information and other DDI management tools for guiding healthcare providers in managing DDIs.

Dosing recommendation of nirmatrelvir/ritonavir using an integrated population pharmacokinetic analysis.

Protease inhibitor nirmatrelvir coadministered with ritonavir as a pharmacokinetic enhancer (PAXLOVID™; Pfizer Inc) became the first orally bioavailable antiviral agent granted Emergency Use Authorization in the United States in patients ≥12 years old with mild to moderate coronavirus disease 2019 (COVID-19). This population pharmacokinetic analysis used pooled plasma nirmatrelvir concentrations from eight completed phase I and II/III studies to characterize nirmatrelvir pharmacokinetics when coadministered with ritonavir in adults with/without COVID-19. Influence of covariates (e.g., formulation, dose, COVID-19) was examined using a stepwise forward selection (α = 0.05) and backward elimination (α = 0.001) approach. Simulations with 5000 subjects for each age and weight group and renal function category were performed to support dosing recommendations of nirmatrelvir/ritonavir for adults with COVID-19 and guide dose adjustments for specific patient populations (e.g., renal insufficiency, pediatrics). The final model was a two-compartment model with first-order absorption, including allometric scaling of body weight and dose-dependent absorption (power function on relative bioavailability). Nirmatrelvir clearance (CL) increased proportionally to body surface area-normalized creatinine CL (nCLCR) up to 70 ml/min/1.73 m2 and was independent of nCLCR above the breakpoint. Significant covariates included carbamazepine or itraconazole coadministration as markers for drug interactions, COVID-19 on CL, formulation on relative bioavailability, and age on central volume of distribution. Simulation results support current dosing recommendations of nirmatrelvir/ritonavir 300/100 mg twice daily (b.i.d.) in adults with normal renal function or mild impairment and pediatrics (12 to <18 years) weighing ≥40 kg and nirmatrelvir/ritonavir 150/100 mg b.i.d. in adults with moderate renal impairment.

Pharmacokinetics of sulfobutylether-ß-cyclodextrin (SBECD) in subjects on hemodialysis.

BACKGROUND: The disposition of sulfobutylether-ß-cyclodextrin (SBECD), the solubilizing excipient in intravenous (i.v.) voriconazole, was assessed in seven male subjects with end-stage renal disease on hemodialysis and six subjects with normal renal function. METHODS: All subjects received twice-daily i.v. voriconazole at the standard voriconazole dose [6 mg/kg (96 mg/kg SBECD) every 12 h (Q12h) on Day 1 followed by 3 mg/kg (48 mg/kg SBECD) Q12h on Days 2-4, with a single i.v. dose on the morning of Day 5]. Subjects were sampled at selected pre-dose trough times, at selected times after infusions and intensively on Day 3 (non-dialysis) and Day 4 (dialysis with high-flux membranes). Compartmental analyses were performed by NONMEM. RESULTS: SBECD disposition was characterized by a two-compartment model. In renal failure, mean central (V(1)) and peripheral compartment volumes (V(2)) were 9.9 and 6.5 L, respectively. In normal subjects, V(1) and V(2) were 9.6 and 5.2 L, respectively; SBECD clearance (CL) was 130 mL/min. CL in renal failure off-dialysis was 2.6 and 48 mL/min during dialysis; mean half-life decreased from 79 to 5 h during dialysis (normal subjects: 2.1 h). CONCLUSION: Hemodialysis can significantly reduce levels of SBECD in subjects with end-stage renal disease.

Lack of an Effect of Supratherapeutic Dose of Venlafaxine on Cardiac Repolarization in Healthy Subjects.

This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24 hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3 hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.

Pharmacokinetics of Oral Nirmatrelvir/Ritonavir, a Protease Inhibitor for Treatment of COVID-19, in Subjects With Renal Impairment.

Nirmatrelvir coadministered with ritonavir is highly efficacious in reducing the risk of coronavirus disease 2019 (COVID-19) adverse outcomes among patients at increased risk of progression to severe disease, including patients with chronic kidney disease. Because nirmatrelvir is eliminated by the kidneys when given with ritonavir, this phase I study evaluated the effects of renal impairment on pharmacokinetics, safety, and tolerability of nirmatrelvir/ritonavir. Participants with normal renal function (n = 10) or mild, moderate, or severe renal impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose with 100 mg ritonavir given 12 hours before, together with and 12 and 24 hours after the nirmatrelvir dose. Systemic nirmatrelvir exposure increased with increasing renal impairment, with mild, moderate, and severe renal impairment groups having respective adjusted geometric mean ratio areas under the plasma concentration-time profile from time 0 extrapolated to infinite time of 124%, 187%, and 304% vs. the normal renal function group. Corresponding ratios for maximum plasma concentration were 130%, 138%, and 148%. Apparent clearance was positively correlated with estimated glomerular filtration rate, and geometric mean renal clearance values were particularly lower for the moderate (47% decrease) and severe (80% decrease) renal impairment groups vs. the normal renal function group. Nirmatrelvir/ritonavir exhibited an acceptable safety profile; treatment-related adverse events were mild in severity, and there were no significant findings regarding laboratory measurements, vital signs, or electrocardiogram assessments. These findings led to a dose reduction recommendation for nirmatrelvir/ritonavir in patients with moderate renal impairment (150/100 mg nirmatrelvir/ritonavir instead of 300/100 mg twice daily for 5 days). NCT04909853.

Pharmacokinetics of voriconazole administered concomitantly with fluconazole and population-based simulation for sequential use.

In clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor metabolizers of CYP2C19. The study consisted of 4-day voriconazole-only and 5-day voriconazole-plus-fluconazole treatments, separated by a 14-day washout. Voriconazole pharmacokinetics were determined by noncompartmental analyses. A physiologically based pharmacokinetic model was developed in Simcyp (Simcyp Ltd., Sheffield, United Kingdom) to predict the magnitude of drug interaction should antifungal therapy be switched from fluconazole to voriconazole, following various simulated lag times for the switch. In CYP2C19 extensive metabolizers, fluconazole increased the maximum plasma concentration and the area under the plasma concentration-time curve (AUC) of voriconazole by 57% and 178%, respectively. In poor metabolizers, however, voriconazole pharmacokinetics were unaffected by fluconazole. The simulations based on pharmacokinetic modeling predicted that if voriconazole was started 6, 12, 24, or 36 h after the last dose of fluconazole, the voriconazole AUC ratios (sequential therapy versus voriconazole only) after the first dose would be 1.51, 1.41, 1.28, and 1.14, respectively. This suggests that the remaining systemic fluconazole would result in a marked drug interaction with voriconazole for ≥ 24 h. Although no safety issues were observed during coadministration, concomitant use of fluconazole and voriconazole is not recommended. Frequent monitoring for voriconazole-related adverse events is advisable if voriconazole is used sequentially after fluconazole.

Lack of an effect of standard and supratherapeutic doses of linezolid on QTc interval prolongation.

A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.

Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.

This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).

The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profile of AZ. Combined QTc findings from electrocardiograms taken during oral and i.v. pharmacokinetic-pharmacodynamic studies of AZ suggest that clinically meaningful QTc prolongation is unlikely. Findings from several observational studies were heterogeneous and not as consistent as results from at least two large randomized controlled trials (RCTs). The QTc findings presented and observational data from studies with large numbers of events are not consistent with either a proarrhythmic action of AZ or an increase in frequency of CV deaths. Well-powered RCTs do not suggest a presence of increased risk of CV or sudden cardiac death after short-term or protracted periods of AZ usage, even in patients at higher risk from pre-existing coronary disease.

Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor. * Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs. * As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them. WHAT THIS STUDY ADDS: * Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean C(max), and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively. * Co-administration was generally safe and well tolerated in healthy subjects. * These changes are not likely to be clinically relevant, thus no dose adjustment is necessary. AIMS: To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir. METHODS: In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1-3 raltegravir 400 mg q12h, days 4-5 washout, days 6-11 maraviroc 300 mg q12h, and days 12-14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters. RESULTS: For maraviroc, the test/reference % ratio (95% CI) for AUC(tau) was 85.8 (78.7, 93.5), for C(max) was 79.5 (64.8, 97.5) and for C(min) was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC(tau) was 63.3 (41.0, 97.6), for C(max) was 66.8 (37.1, 120.0) and for C(min) was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC(tau) divided by 12) were >100 ng ml(-1), the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C(min) decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance. CONCLUSIONS: Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.

Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19.

Azithromycin (AZ) is a broad-spectrum macrolide antibiotic with a long half-life and a large volume of distribution. It is primarily used for the treatment of respiratory, enteric, and genitourinary bacterial infections. AZ is not approved for the treatment of viral infections, and there is no well-controlled, prospective, randomized clinical evidence to support AZ therapy in coronavirus disease 2019 (COVID-19). Nevertheless, there are anecdotal reports that some hospitals have begun to include AZ in combination with hydroxychloroquine or chloroquine (CQ) for treatment of COVID-19. It is essential that the clinical pharmacology (CP) characteristics of AZ be considered in planning and conducting clinical trials of AZ alone or in combination with other agents, to ensure safe study conduct and to increase the probability of achieving definitive answers regarding efficacy of AZ in the treatment of COVID-19. The safety profile of AZ used as an antibacterial agent is well established.1 This work assesses published in vitro and clinical evidence for AZ as an agent with antiviral properties. It also provides basic CP information relevant for planning and initiating COVID-19 clinical studies with AZ, summarizes safety data from healthy volunteer studies, and safety and efficacy data from phase II and phase II/III studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of AZ and CQ in combination. This paper may also serve to facilitate the consideration and use of a priori-defined control groups for future research.

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects.

The effect of steady-state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single-center, randomized, 3-way crossover, double-blind, placebo- and moxifloxacin-controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12-lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed-effect model with sequence, period, treatment, time, and treatment-by-time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure-response was assessed using linear mixed-effect modeling. Fifty-four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10-millisecond significance threshold at the 4-hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635-11.666]). In the exposure-response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady-state 400-mg/day dose.

In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin.

Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.