Mean Apparent Total Clearance Research Articles

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral AL01211 in Healthy Chinese Volunteers.

Aberrant accumulation of glycosphingolipids (GSLs) in the lysosome leads to GSL storage diseases. Glucosylceramide synthase inhibitors (GCSi) have the potential to treat several GSL storage diseases by reducing the synthesis of the disease-causing GSLs. AL01211 is a potent oral GCSi under investigation for Type 1 Gaucher disease and Fabry disease. Here, we evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of AL01211 in healthy Chinese volunteers. AL01211 was tested in a Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms. Results of AL01211 demonstrated dose-dependent pharmacokinetics, rapid absorption (median time to maximum plasma concentration [tmax] 2.5-4 hours), relatively slow clearance rate (mean apparent total clearance from plasma [CL/F] 88.3-200 L/h) and the mean terminal half-life above 30 hours. Repeated once-daily oral administration of AL01211 for 14 days had an approximately 2-fold accumulation, reaching steady-state levels between 7 and 10 days, and led to a 73% reduction in plasma glucosylceramide (GL1) on Day 14. AL01211 was safe and well tolerated, with no identified serious adverse events. AL01211 showed a favorable pharmacokinetic, pharmacodynamics, safety, and tolerability profile in healthy Chinese volunteers. These data support the further clinical development of AL01211 as a therapy for GSL storage diseases. Clinical Trial Registry no. CTR20221202 ( http://www.chinadrugtrials.org.cn ) registered on 6 June 2022 and ChiCTR2200061431 ( http://www.chictr.org.cn ) registered on 24 June 2022.

A Comparative Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of Azacitidine Following Subcutaneous (SC) and Oral Administration in Subjects with Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML), Results From a Phase 1 Study.

Abstract 1772Poster Board I-798 BackgroundParenteral azacitidine significantly improves overall survival in patients with higher-risk MDS and WHO AML (20-30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009;10:223). An oral azacitidine formulation is in development. A Phase 1, “3+3”, dose-escalation study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, PK and PD profiles of SC and increasing doses of orally-administered azacitidine in subjects with MDS or AML (not candidates for other therapies) by WHO criteria. In this study, each subject served as their own control and received SC azacitidine in Cycle 1 followed by oral azacitidine in subsequent cycles (Cycle 2+). PK and PD were evaluated in blood, following SC and oral administration. DNA methylation patterns in blood pre- and post-treatment (SC and oral) were explored to build an understanding of how DNA methylation may relate to azacitidine PK parameters. MethodsAzacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. PK parameters were derived from azacitidine concentrations in plasma and urine collected after the first and last dose. Samples collected in Cycles 1 and 2 were assayed for DNA methylation using Illumina's Infinium Human Methylation27 BeadArrays, which provide methylation levels for >27,000 CpG loci. A linear models for microarray analysis (LIMMA) was performed to identify loci that were differentially methylated from baseline versus (vs.) each post-treatment timepoint across subjects. To identify loci whose methylation levels were modulated in relation to azacitidine PK parameters, Spearman's correlation coefficients were computed for azacitidine exposure (AUCinf) or peak plasma concentration (Cmax) vs. the fold change in methylation at Day 15 for each locus across subjects. ResultsTo date, PK data have been generated for 31 of 45 enrolled subjects. Oral doses evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. Following SC and oral administrations, azacitidine was rapidly absorbed and reached Cmax within 0.5 hr (0.2, 1.1) and 1.0 hr (0.5, 2.5) post-dose (median [min, max]), respectively. The concentration vs. time profiles declined in a pseudo bi-phasic manner, with a mean elimination half-life of 1.8 ± 1.1 hr and 0.74 ± 0.28 hr for SC and oral, respectively. For SC azacitidine, mean AUCinf = 1090 ± 470 hr*ng/mL, mean apparent total clearance (CL/F) = 170 ± 130 L/hr, and mean apparent volume of distribution (Vd/F) = 445 ± 450 L. Following either SC or oral treatments, azacitidine recovery in urine was very small relative to dose (<2%). The median (min, max) relative oral bioavailability was 13% (5%, 35%) and the median (min, max) exposure (AUCinf) of oral azacitidine compared to SC was 31% (14%, 74%) (except for 1 subject whose oral exposure was 167% SC). CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism; Vd/F was 9- to 11-fold greater than total body water suggesting extensive tissue distribution. To date, PD data have been generated for 8 and 3 subjects during SC and oral treatment, respectively. The numbers of significantly (p<0.010) hypomethylated loci peaked at Day 15 of Cycle 1 (SC) with over 4000 loci hypomethylated and at Day 15 of Cycle 2 (oral) with less than 300 loci hypomethylated vs. either baseline or Day 1 of Cycle 2. Approximately 260 hypomethylated loci are common to both groups. Spearman correlation analyses showed that DNA hypomethylation for 252 and 98 loci were correlated (r>0.8) with Day 1 SC and oral azacitidine AUCinf and Cmax, respectively. ConclusionFollowing oral administration, azacitidine demonstrated increased exposure with increasing dose. At dose levels tested to date, oral exposures are lower than SC. Non-renal clearance (hepatic and extra-hepatic) is the major elimination pathway with renal elimination playing a minor role. Changes in DNA methylation were observed in the blood of MDS/AML subjects following SC and oral azacitidine treatment, and a set of CpG loci was identified for which these changes were associated with AUCinf and/or Cmax. PK/PD correlations identified in these initial subjects will be further explored. The lower exposures and PD effects observed with oral vs. SC azacitidine on a 7-day schedule provide rationale for testing extended schedules and BID dosing in future trials. DisclosuresMacBeth:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ning:Celgene: Employment, Equity Ownership. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Skikne:Celgene: Employment. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Ward:Celgene: Employment, Equity Ownership.

Pharmacokinetics, Pharmacodynamics and Safety of Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase, in a Dose Escalation Study in Healthy Subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout. To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects. In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3-14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study. Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5-1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10-120 mg dose range, with a mean apparent total clearance of 10-12 L/h and an apparent volume of distribution at steady state of 33-64 L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120 mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22-44% of the dose) and oxidation (2-8%) with only 1-6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34-3.88 mg/dL) for all doses and was dose linear for the 10-120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity. Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.

Single-Dose Pharmacokinetics of Nateglinide in Subjects with Hepatic Cirrhosis

This single-dose, open-label, parallel-group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis ande matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half-lives were comparable. Mean ± SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 ± 4.9 vs. 5.6 ± 1.3 μg/ml; AUC(0-t), 18.5 ± 7.5 vs. 14.2 ± 2.1 μg·h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein-bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.

Single‐Dose Pharmacokinetics of Nateglinide in Subjects with Hepatic Cirrhosis

This single-dose, open-label, parallel-group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis and 8 matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half-lives were comparable. Mean +/- SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 +/- 4.9 vs. 5.6 +/- 1.3 micrograms/ml; AUC(0-t), 18.5 +/- 7.5 vs. 14.2 +/- 2.1 micrograms.h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein-bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.

Pharmacokinetics of tolfenamic acid in pediatric patients after single oral dose.

The pharmacokinetics of tolfenamic acid, a non-steroidal anti-inflammatory drug, were determined following administration of a 1 mg/kg single oral dose of tolfenamic acid suspension to 6 feverish children. Their ages were from 2-14 years (mean 7.5 years) and their weights were from 12-50 kg (mean 29.2 kg). Tolfenamic acid produced a significant fall in temperature (about 2 degrees C) compared to the initial value before oral intake of the drug and was well tolerated without adverse effects. Blood samples for determination of tolfenamic acid concentrations in plasma were obtained at timed intervals for up to 8 h post-dose. Plasma concentrations of tolfenamic acid were determined using a reversed phase HPLC method and pertinent pharmacokinetic parameters were estimated by model-independent standard methods and were the following: the mean peak plasma concentration (Cmax +/- SEM) was 1.09 +/- 0.44 micrograms/ml (range, 0.65-1.63 micrograms/ml) and the mean time (tmax +/- SEM) to reach peak plasma concentration was 1.4 +/- 0.4 h (range, 0.5-3.0 h). The mean area under the plasma concentration-time curve (AUC0-->infinity +/- SEM) was 4.61 +/- 0.40 micrograms.h/ml (range, 2.74-5.98 micrograms.h/ml), the mean elimination half-life (t1/2 +/- SEM) was 2.82 +/- 0.21 h (range, 2.19-3.40 h) and the mean apparent total clearance (CL/F +/- SEM) was 3.83 +/- 0.41 ml/min/kg (range, 2.79-6.08 ml/min/kg).

Disposition of Intramuscular Cefonicid in Elderly Patients

To examine the disposition of intramuscular (IM) cefonicid in elderly patients with bacterial pneumonia. Pharmacokinetic study. A 620-bed university-affiliated long-term care institution with its own 39-bed acute care unit. Nine consecutive elderly patients with bacterial pneumonia treated with IM cefonicid. Blood samples were collected on the seventh day of therapy over a 24-hour period and analyzed by high performance liquid chromatography. Pharmacokinetics parameters (volume of distribution, half-life, and clearance) and protein binding were calculated. Clinical outcome of IM cefonicid therapy was also noted. The estimated creatinine clearance (CIcr) ranged from 32 to 145 mL/min. Peak cefonicid serum concentrations occurred at 0.5-1.5 hours, with a mean value of 118 +/- 41 micrograms/mL. Cefonicid concentrations declined monoexponentially to 57 +/- 16 micrograms/mL at 12 hours and 28 +/- 14 micrograms/mL at 24 hours. The mean apparent distribution volume was 0.2 +/- 0.07 L/kg, and the mean apparent total clearance was 15 +/- 12 mL/min. The half-life ranged from 3.1 to 38 hours. A linear correlation was noted between Clcr and cefonicid clearance (r = 0.99). Cefonicid absorption was variable among these patients, and the serum half-life was longer than previous values noted in younger patients with similar degree of renal dysfunction. Pharmacokinetic and clinical outcome data from our study group indicate the potential role of IM cefonicid in treating elderly patients with bacterial pneumonia.

Pharmacokinetic evaluation of drug interactions with anti-HIV drugs, II: Effect of 2',3'-dideoxyinosine (ddI) on zidovudine kinetics in monkeys.

The pharmacokinetic basis of a drug interaction between zidovudine (AZT) and 2',3'-dideoxyinosine (ddI) was investigated in normal monkeys. Five animals received 20 mg/kg of AZT intragastrically in the absence and presence of ddI. ddI was administered intravenously to produce steady-state ddI plasma concentrations for 30 min. Plasma and urine samples were analyzed for AZT, its major glucuronide metabolite, GAZT, and ddI by high-performance liquid chromatography (HPLC). Resultant AZT and GAZT concentration data were analyzed by noncompartmental methods. Statistical analysis indicated no differences in AZT's apparent total clearance, apparent volume of distribution at steady-state, and elimination half-life due to ddI, however, the mean apparent total clearance decreased from 2.92 to 1.67 L/h/kg, and the mean apparent volume of distribution at steady-state decreased from 5.79 to 3.43 L/kg in the presence of ddI. Incomplete urine collections in most animals prevented conclusions from being made about ddI's effect on renal elimination parameters. Nonetheless, the urinary GAZT/AZT ratio, a parameter not influenced by incomplete urine collection, was significantly reduced in the presence of ddI. Although additional studies will be useful to characterize the full importance of the interaction, there is evidence to suggest that both renal and metabolic elimination of AZT and renal elimination of GAZT may be inhibited by ddI.

Pharmacokinetics and sputum penetration of enoxacin after twice daily oral dosing for seven days.

The ability of enoxacin to penetrate into sputum and its distribution and elimination characteristics after dosing to steady state were determined in six subjects with permanent tracheostomies. At steady state the mean trough level of enoxacin in sputum was 1.75 +/- 0.70 mg/kg (mean +/- S.D.), and the corresponding level in plasma was 1.23 +/- 0.32 mg/l. The mean peak sputum concentration at steady state was 7.12 +/- 4.21 mg/kg with the corresponding level in plasma being 4.54 +/- 1.34 mg/l. The ratio of the mean trough concentration of enoxacin in sputum to that in plasma was 1.42 +/- 0.36, and the ratio of the mean peak concentrations was 1.67 +/- 1.07. The pharmacokinetics of enoxacin in sputum were similar to those in plasma, the only significant difference being between the mean times to reach peak concentration (T-max) which were 2.62 +/- 1.04 and 0.92 +/- 0.44 h in sputum and plasma respectively (P less than 0.01). After reaching steady state, the mean area under the plasma time-concentration curve (AUC) from 0 to 12 h (the dosing interval) was 26.6 +/- 5.9 mg/h/l, and the mean AUC (0-12) for sputum was 40.9 +/- 21.8 mg/h/kg. The mean apparent total clearance was 259.6 +/- 48.8 ml/min and the mean apparent volume of distribution was 169.6 +/- 30.51. Enoxacin exhibits a high degree of penetration into sputum which may prove useful in the treatment of bacterial infections of the respiratory tract.