Oral Bioavailability of Candesartan Cilexetil Suspension

2007 ◽  
Vol 23 (5) ◽  
pp. 270-274 ◽  
Author(s):  
Renli Teng ◽  
Anna-Carin Hansson ◽  
Inger Börjesson
Keyword(s):  
Candesartan Cilexetil ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Relative Bioavailability ◽  
Maximum Plasma ◽  
Open Label ◽  
Serious Adverse Events ◽  
Time To Peak ◽  
Period 2 ◽  
Elimination Half

Background: Candesartan cilexetil is a prodrug that is converted to candesartan during absorption from the gastrointestinal tract. Candesartan is a potent, orally active, specific angiotensin II type 1 receptor antagonist that has become a well-accepted treatment for hypertension. Pediatric patients often require alternative dosage forms, as candesartan cilexetil is not yet commercially available as a liquid formulation. Objective: To determine the relative bioavailability of candesartan by comparing a candesartan cilexetil tablet (reference formulation) with an oral candesartan cilexetil suspension (test formulation). Methods: In an open-label, randomized, 2 period, 2 treatment crossover study, 24 healthy volunteers were given a 32 mg candesartan cilexetil tablet and a 32 mg candesartan cilexetil suspension with a 7 day washout period between treatments. Results: Pharmacokinetic analyses showed that the mean relative bioavailability of the candesartan cilexetil commercial 32 mg tablet compared with the suspension of 32 mg candesartan cilexetil was 93%. The 90% CIs of the plasma AUC for the tablet versus suspension (0.861 and 0.998, respectively) were well within the bioequivalence criteria of 80–125%. Administration of candesartan cilexetil suspension was associated with a 17% increase in the maximum plasma concentration (Cmax) relative to the tablet administration (643 vs 523 nM/L, respectively). The 90% CIs on the ratio of mean Cmax for the tablet and suspension were 0.738 and 0.914, respectively. Mean time to peak plasma concentrations (tmax) after suspension administration was 3.1 hours, whereas the tablet resulted in a mean tmax of 3.9 hours. No significant differences in elimination half-life were observed between the 2 formulations. Both formulations were well tolerated, and no serious adverse events were reported. Conclusions: These results demonstrate that administration of candesartan cilexetil suspension achieves an extent of absorption and tolerability that is comparable with those of orally administered candesartan cilexetil tablets.

Phase I/IIa, randomized, open-label, drug-drug interaction study of trabectedin and rifampin in patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13512-e13512 ◽  
Author(s):  
Arthur P. Staddon ◽  
Trilok V. Parekh ◽  
Roland Elmar Knoblauch ◽  
Chi Keung ◽  
Apexa Bernard ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Locally Advanced ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Maximum Plasma ◽  
Metabolic Clearance ◽  
Open Label ◽  
Time Curve ◽  
Elimination Half ◽  
Cyp3a4 Inducer

e13512 Background: Trabectedin (Yondelis; T) is a tetrahydroisoquinoline compound initially isolated from the marine tunicate, Ecteinascidia turbinata, and currently produced synthetically. It is primarily metabolized by the cytochrome P450 (CYP)3A4 enzyme. Thus, potent inducers or inhibitors of this enzyme may alter the plasma concentrations of T. This study assessed the effects of rifampin (R), a strong CYP3A4 inducer, on the pharmacokinetics (PK) and safety of T. Methods: In this 2-way crossover study, patients (≥18 years of age) with locally advanced or metastatic disease were randomized (1:1) to receive one of the 2 treatment sequences: sequence 1: R plus T followed 28 days later by T; sequence 2: T followed 28 days later by R plus T. During each sequence, R (600 mg/day) was administered for 6 consecutive days and T (1.3 mg/m2, IV) was administered over a 3 hour infusion. Dexamethasone (20 mg, IV) was administered before T administration. PK and safety of T were evaluated with and without coadministration of R. Results: Of the 11 enrolled patients, 8 were PK evaluable. Coadministration of R with T decreased mean maximum plasma concentration (Cmax) by approximately 22% and mean area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) by approximately 31% (Table 1). Coadministration of R with T also resulted in 23% shorter elimination half-life. Overall, the safety profile of T was comparable when administered alone or with R. Conclusions: In comparison with T alone, coadministration of R resulted in reduced systemic exposure of T in these 8 patients, as measured by Cmax and AUClast. The coadministration of potent inducers of CYP3A4 with T may increase the metabolic clearance of T. Clinical trial information: NCT01273480. [Table: see text]

Bioavailability of Temazepam: Comparison of Four 7.5-mg Capsules with a Single 30-mg Capsule

1993 ◽  
Vol 27 (6) ◽  
pp. 695-699 ◽  
Author(s):  
Craig Abolin ◽  
Dar-Shong Hwang ◽  
Frank Mazza
Keyword(s):  
Peak Concentration ◽  
Dosage Form ◽  
Peak Plasma ◽  
Statistical Significance ◽  
Plasma Concentrations ◽  
Latin Square ◽  
Open Label ◽  
Time To Peak ◽  
Rate Of Absorption ◽  
The Mean

OBJECTIVE: To compare the bioavailability of four temazepam 7.5-mg capsules (Restoril, Sandoz Pharmaceuticals) with that of a single temazepam 30-mg capsule. DESIGN: Single-dose, open-label, two-period, crossover (replicated Latin square). SETTING: Domiciled environment for clinical testing. PARTICIPANTS: Twenty-six healthy male volunteers aged 18–40 years; 25 completed the study. INTERVENTIONS: Subjects randomly received either four temazepam 7.5-mg capsules or one temazepam 30-mg capsule. Blood samples were drawn at various time points after each period (0-48 h), and analyzed for plasma concentration of temazepam. The washout period between doses was five days. MAIN OUTCOME MEASUREMENTS: Five parameters of both dosage forms were compared: (1) area under curve (AUC), (2) peak concentration (Cmax), (3) time to peak concentration (Tmax), (4) apparent rate constant for absorption, and (5) lag time for appearance of drug in plasma. Statistical procedures included ANOVA, power analysis, and confidence limits. RESULTS: The mean AUC for the four 7.5-mg capsules and one 30-mg capsule differed by less than 2 percent and the mean Cmax differed by less than 14 percent for the two dosage strengths; neither of these differences reached statistical significance (p>0.05). The 7.5-mg capsules reached peak plasma concentrations significantly faster than the 30-mg dosage form (mean Tmax 1.18 and 1.73 h, respectively; p=0.01). CONCLUSIONS: The two formulations of temazepam were bioequivalent with respect to the extent of bioavailability. Regarding the rate of absorption, however, the 7.5-mg capsules reached peak plasma concentrations significantly faster than the 30-mg dosage form.

scholarly journals Comparative pharmacokinetics and absolute bioavailabilities of two enrofloxacin generic preparations after single intracrop bolus administrations to broiler chickens

2016 ◽  
Vol 4 (2) ◽  
pp. 115
Author(s):  
Nasser Ehmeza ◽  
Abdelrazzag Elmajdoub ◽  
Abubakr El-Mahmoudy
Keyword(s):  
Broiler Chickens ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Oral Solution ◽  
Pharmacokinetic Analysis ◽  
Maximum Plasma ◽  
Time To Peak ◽  
Elimination Half ◽  
Acceptance Range

The pharmacokinetics and absolute bioavailabilities of two generics of enrofloxacin (ENRO) 10% oral solution formulation at a dose of 10 mg/Kg body weight were compared after single intracrop (i.c.) bolus administrations in reference to single intravenous (i.v.) standard ENRO administration in broilers using a randomized parallel design. The two tested formulations were Enrol® (Medmac®, Amman, Jordan) as ENRO-A and Syvaquinol® (Syva®, Leon, Spain) as ENRO-B 10% oral solutions. An HPLC assay using pure ENRO base as a standard was used to measure concentrations of ENRO from the selected sources in plasma collected at predetermined time points up to 24 hours. The pharmacokinetic analysis of the C-T data was performed using non-compartmental analysis based on statistical moment theory with the help of computerized WinNonlin program (Version 5.3, Pharsight® Corporation, St. Louis, USA). The maximum plasma concentrations (Cmax) for ENRO-A and ENRO-B were 1.61 ± 0.203 and 1.79 ± 0.283 μg/mL, respectively, attained at time to peak (Tmax) of 2 h. Elimination half-lives (t1/2β) were 8.391 ± 0.312 and 8.458 ± 0.906 h, respectively. While areas under plasma concentration-time curves (AUC0-∞), and systemic bioavailabilities (F) were 12.744 ± 2.951 and 14.354 ± 2.85 mg.h/L; and 78.96 ± 6.728 and 88.94 ± 10.89 % for ENRO-A and ENRO-B, respectively. It could be concluded that despite the superior pharmacokinetic profile of ENRO-B over ENRO-A, however, both generics were within the FDA and EMA bioequivalence acceptance range of 80%–125% and thus can be used as interchangeable therapeutic agents in chickens.

Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽  
2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 17-27 ◽  
Author(s):  
SD Silberstein ◽  
J Schoenen ◽  
H Göbel ◽  
HC Diener ◽  
AH Elkind ◽  
...  
Keyword(s):  
Adverse Events ◽  
North American ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Plasma Concentrations ◽  
International Study ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

Abstract 527: Vorapaxar Does Not Increase Bleeding Time

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Walter Kraft ◽  
Jocelyn Gilmartin ◽  
Derek L Chappell ◽  
Srikanth Nagalla ◽  
Uhlas P Naik ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Clinical Trial Data ◽  
Open Label ◽  
Period 2 ◽  
Parallel Group ◽  
The Us ◽  
Surgical Bleeding ◽  
Group 2

Vorapaxar is a novel PAR-1 inhibitor approved in the US and EU to reduce risk of thrombotic CV events in patients with a history of MI, and in the US also in patients with PAD. It does not affect coagulation tests (TT, PT, aPTT, ACT, ECT). Aspirin and P2Y 12 inhibitors prolong human bleeding time (BT); does vorapaxar? Methods: In this randomized, active controlled, parallel group, 2-period, single-blind, open-label trial, healthy men (n=31) and women (n=5), in Period 1, received either 81 mg aspirin (ASA) QD for 7 days (N=18), or a 7 day regimen of vorapaxar (N=18) achieving steady state plasma concentrations equivalent to chronic 2.5 mg QD doses. In Period 2, each group added 7 days of the therapy alternate to that of Period 1 without washout. BT and platelet aggregation (PA) using arachidonic acid, ADP, and TRAP agonists were collected predose in Periods 1 (baseline) and 2, and 24 h after Period 2 last dose. A linear mixed effects model with fixed effect for treatment analyzed data. Results: BT geometric mean ratio (90% CI) for (vorapaxar/baseline) was 1.01 (0.88, 1.15), (ASA/baseline) was 1.32 (1.15, 1.51), (vorapaxar+ASA/vorapaxar) was 1.47 (1.26, 1.70), (vorapaxar+ASA/ASA) was 1.12 (0.96, 1.30). Each antiplatelet inhibited PA only as expected. See figure. Conclusions: Unlike ASA, vorapaxar did not prolong BT compared to baseline. When given with ASA, there is a slight numerical increase in BT beyond that of ASA. Implications for clinical spontaneous or surgical bleeding await further analyses of clinical trial data.

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

1994 ◽  
Vol 12 (9) ◽  
pp. 1902-1909 ◽  
Author(s):  
D R Budman ◽  
L N Igwemezie ◽  
S Kaul ◽  
J Behr ◽  
S Lichtman ◽  
...  
Keyword(s):  
High Performance ◽  
Peak Plasma ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
High Dose ◽  
Maximum Plasma ◽  
Rapid Infusion ◽  
Etoposide Phosphate

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Relative bioavailability of an extemporaneously prepared aprepitant oral suspension in healthy adults

2019 ◽  
Vol 25 (8) ◽  
pp. 1907-1915
Author(s):  
Priya Patel ◽  
Paul C Nathan ◽  
Scott E Walker ◽  
Sue Zupanec ◽  
Jocelyne Volpe ◽  
...  
Keyword(s):  
Least Squares ◽  
Plasma Concentrations ◽  
Relative Bioavailability ◽  
Oral Suspension ◽  
Serious Adverse Events ◽  
Time Curve ◽  
Time Zero ◽  
Oral Liquid ◽  
Health Canada ◽  
Adult Volunteers

Purpose Use of aprepitant for chemotherapy-induced nausea and vomiting prophylaxis in patients unable to swallow capsules is hindered by the lack of a commercially available oral liquid formulation in many jurisdictions. A stable oral suspension can be extemporaneously prepared using commercially available capsules. We aimed to determine the bioavailability of this aprepitant suspension relative to the capsule. Methods This two-period crossover study enrolled 17 healthy adult volunteers. Volunteers received a single 125 mg aprepitant dose during each study period. Order of formulation presentation (capsule vs suspension first) was randomized. Thirteen blood samples were collected over a 48-h period. Aprepitant plasma concentrations were determined using liquid chromatography-mass spectroscopy. Relative bioavailability was defined as the geometric least squares mean ratio for area under the concentration versus time curve (AUC) from time zero to infinity of the aprepitant suspension versus the capsule. Bioequivalence, defined as per Health Canada guidelines, was assessed as a secondary aim. Results Relative bioavailability of the aprepitant suspension was 82.3% (90% CI: 69.09-98.00%). Bioequivalence was not established: geometric least squares mean ratios (suspension/capsule) for AUC time zero to 48 h and maximum concentration were 87.8% (90% CI: 75.48–102.16%) and 86.1% (90% CI: 75.59–98.16%), respectively. No serious adverse events were observed. Conclusions With a relative bioavailability of 82.3%, the extemporaneous aprepitant oral suspension was well-absorbed relative to the capsule. Though not bioequivalent to the oral capsule, the clinical use of this aprepitant oral suspension in adult and pediatric patients unable to swallow capsules is likely to be effective and safe.

scholarly journals Catechin Bioavailability Is Reduced in Obese Persons Without Altering Gut Microbial-Derived Valerolactones Following Consumption of a Green Tea Extract Confection

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 468-468
Author(s):  
Geoffrey Sasaki ◽  
Yael Vodovotz ◽  
Zhongtang Yu ◽  
Richard Bruno
Keyword(s):  
Green Tea ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Relative Bioavailability ◽  
Green Tea Extract ◽  
Maximum Plasma ◽  
Gut Permeability ◽  
Epicatechin Gallate ◽  
Obesity Status ◽  
Tea Extract

Abstract Objectives Green tea extract (GTE) protects against obesity in rodents by reducing gut permeability that otherwise provokes endotoxemia-mediated inflammation. However, whether obesity affects catechin bioavailability and microbial metabolism is unknown. We hypothesized that obesity will reduce catechin bioavailability by increasing microbial biotransformation of catechins. Methods Obese persons (n = 10 M/7F; 33.5 ± 0.7 kg/m2) and age-matched healthy persons (n = 10 M/9F; 21.7 ± 0.4 kg/m2) completed a pharmacokinetics (PK) trial in which a GTE confection [290 mg epigallocatechin gallate (EGCG), 87 mg epigallocatechin (EGC), 39 mg epicatechin (EC), 28 mg epicatechin gallate (ECG)] was ingested prior to collecting plasma at 0, 0.25, 0.5, 1, 2, 3, 5, 8, 10, and 12 h and urine from 0–4, 4–8, 8–12, and 12–24 h. Stool samples were collected and gut permeability was assessed prior to the 12-h PK trial. Plasma and urinary catechin/catechin-derived microbial metabolites were assessed following enzymatic hydrolysis by LC-MS. Results Regardless of health status, relative bioavailability, based on plasma area under the curve (AUC0–12 h), of GTE catechins were: EGCG > EGC > ECG > EC. However, obese persons had 24–27% lower plasma AUC0–12 h for the four catechins compared to lean persons (P < 0.05). They also had 18–36% lower maximum plasma concentrations (Cmax) of GTE catechins but 12 h plasma catechin concentrations were unaffected by obesity status (P > 0.05). 3ʹ,4ʹ-γ-valerolactone (3,4-VL) was detected in the plasma of all participants, while 3ʹ,4ʹ,5ʹ-γ-valerolactone (3,4,5-VL) was detected in 74% and 82% of lean and obese persons, respectively. Plasma AUC0–12 h for these VL metabolites did not differ by obesity status. EGC, EC, 3,4-VL, and 3,4,5-VL, but not EGCG and ECG, were primarily present in urine and urinary total VLs were increased compared with total urinary catechins. However, 24-h urinary excretion of catechins and VLs were unaffected by obesity. Conclusions Obesity reduces GTE catechin bioavailability and Cmax independent of any change in VL metabolite appearance or urinary elimination of catechins, suggesting a gut-level mechanism that limits catechin absorption. Funding Sources Supported by USDA-NIFA and the Foods for Health Discovery Theme at The Ohio State University.

scholarly journals Single-Ascending-Dose Pharmacokinetics and Safety of the Novel Broad-Spectrum Antifungal Triazole BAL4815 after Intravenous Infusions (50, 100, and 200 Milligrams) and Oral Administrations (100, 200, and 400 Milligrams) of Its Prodrug, BAL8557, in Healthy Volunteers

2006 ◽  
Vol 50 (1) ◽  
pp. 279-285 ◽  
Author(s):  
Anne Schmitt-Hoffmann ◽  
Brigitte Roos ◽  
Markus Heep ◽  
Michael Schleimer ◽  
Erhard Weidekamm ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Pathogenic Fungi ◽  
Volume Of Distribution ◽  
The Body ◽  
Water Soluble ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Time Curve ◽  
To Receive

ABSTRACT BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.

scholarly journals Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
Rakesh Chugh ◽  
Mugdha Gupta ◽  
H. David Friedland ◽  
...  
Keyword(s):  
Healthy Adult ◽  
Plasma Concentrations ◽  
Maximum Plasma ◽  
Total Plasma ◽  
Time Curve ◽  
The Third ◽  
Elimination Half ◽  
The Mean ◽  
Repeated Dosing ◽  
Tract Infections

ABSTRACT The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (C max) of 1.02 ± 0.31 μg/ml and 1.39 ± 0.36 μg/ml, respectively; times to C max of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 μg · h/ml. For ELF, the respective AUC0–24 values based on the mean and median concentrations were 224.1 and 176.3 μg · h/ml, whereas for AM, the respective AUC0–24 values were 8,538 and 5,894 μg · h/ml. Penetration ratios based on ELF and total plasma AUC0–24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.)

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