Mean Renal Clearance Research Articles

A Phase I Study To Determine the Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Capivasertib in Healthy Male Participants.

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 μg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.

#2994 Nephrotoxicity post injection of iodized PDC in patients with renal failure in the emergency room

Abstract Background and Aims Nephropathy following injection of iodinated contrast media (PDC) is the leading cause of iatrogenic acute renal failure. Several associated factors have been identified, including renal function before the procedure. Objective To study the incidence of nephrotoxicity post venous-injection of iodinated PDC in patients with impaired renal function. Method This was a prospective, descriptive, single-center study over a six-month period. Patients aged over 14 years and having undergone an injection of iodinated contrast products for diagnostic or therapeutic purposes were included. We excluded patients with stage IV renal insufficiency (Cl ≤ 29 ml/min) with or without indication for extra-renal purification. Nephropathy in this context was defined by an elevation in baseline plasma creatinine of more than 25% in the 48 to 72 hours following injection. Results During the study period, 135 patients were collected with a mean age of 46 ± 18 years and range of 16 to 97 years. The gender ratio was 3.2 with a male predominance. Thirty-two patients had impaired renal function on admission, of which seven patients (5.2%) were known to have chronic renal failure and twenty-five patients (18.5%) had impaired renal function discovered on admission. The mean renal clearance was 90.9 ± 36.3 ml/min with extremes ranging from 30 ml/min to 176 ml/min. More than half of the patients had normal renal function (Stage G1 according to the KDIGO 2022 classification) (n = 79, 58.5%). The incidence of nephropathy post venous-injection of iodized PDCs was 15.6%. 111 patients (82.8%) benefited from per-procedure hydration protocol. In univariate analysis, chronic renal failure or discovered on admission was associated with the risk of worsening renal function with a statistically significant difference, p respectively at 0.007 and 0.009. Furthermore, the correlation between the worsening of renal function as a function of initial plasma creatinine showed that initial plasma creatinine was higher in patients who developed iodinated contrast nephropathy with a statistically significant difference, p = 0.005, a sensitivity of 57% and a specificity of 78%. ROC curve analysis showed an AUC of 0.691; 95% CI [0.567-0.815], with a discriminant Cut off of plasma creatinine at 90.5 µmol/l. Conclusion The incidence of post-iodized PDC injection nephropathy was high in emergency room. Among the independent associated factors identified, chronic renal insufficiency or discovered on admission which requires special precautions, especially through optimal hydration.

A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults.

Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study. This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400mg and to 8 older adults (age ≥65years) at 1400mg. In MAD, doses of 350mg once daily (qd), 350mg twice daily (bid) and 450mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels. BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100mg to 1400mg, mean Cmax and areas under the curve increased less than dose-proportionally. Mean half-life was short (2.4-4.9h), and mean renal clearance was comparable in all doses (4.05-5.05L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%-15% lower for AUCs) compared with young subjects. In MAD, 350 and 450mg bid led to a slight accumulation over 14days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14-deoxypoststerone) were identified and quantified. BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).

Population Pharmacokinetics and Dosing Simulations of Ceftriaxone in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (An ASAP ECMO Study).

BackgroundDespite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting.ObjectiveThe aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO.MethodsSerial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics®. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT>MIC).ResultsIn total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L).ConclusionsDosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01106-x.

Excretion of mephedrone and its phase I metabolites in urine after a controlled intranasal administration to healthy human volunteers.

Mephedrone is a stimulant drug structurally related to cathinone. At present, there are no data available on the excretion profile of mephedrone and its metabolites in urine after controlled intranasal administration to human volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Urine was collected at different timepoints on Day 1 and then on Days 2, 3 and 30. Samples were analysed for the presence of mephedrone and its metabolites, namely, dihydro‐mephedrone, nor‐mephedrone (NOR), hydroxytolyl‐mephedrone, 4‐carboxy‐mephedrone (4‐carboxy) and dihydro‐nor‐mephedrone (DHNM), by a validated liquid chromatography‐tandem mass spectrometry method. All analytes were detected in urine, where 4‐carboxy (Cmax = 29.8 μg/ml) was the most abundant metabolite followed by NOR (Cmax = 377 ng/ml). DHNM was found at the lowest concentrations (Cmax = 93.1 ng/ml). Analytes exhibited a wide range of detection windows, but only 4‐carboxy and DHNM were detectable in all samples on Day 3, extending the detection time of mephedrone use. Moreover, mephedrone had a mean renal clearance of 108 ± 140 ml/min, and 1.3 ± 1.7% of unchanged parent drug was recovered in urine in the first 6 h post administration. It is hoped that this novel information will be useful in future studies involving mephedrone and other stimulant drugs.

Effect of Omecamtiv Mecarbil on the Pharmacokinetics of Metformin, a Probe Substrate for MATE1/MATE2-K, in Healthy Subjects.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure with reduced ejection fraction. The objective of this study was to evaluate the potential for OM to affect the pharmacokinetics of metformin. This was anopen-label, fixed-sequencestudy in 14 healthy subjects.On Day 1, subjects received an 850 mg oral dose of metformin. From Days 4 to 9, subjects received twice-daily 25 mg oral doses of OM tablets. On Day 10, subjects received an 850 mg oral dose of metformin and a single 25 mg tablet of OM. Blood and urine samples were collected up to 36 h post-dose following administration of metformin on Days 1 and 10 to characterize concentrations of metformin in plasma and urine. The ratios of the geometric least square means of metformin coadministered with OM compared to metformin alone were 98.7%, 99.3%, and 110.2% for AUCinf, AUClast, and Cmax, respectively. The mean renal clearance of metformin was similar following metformin administered alone (34.2 L/h) compared to metformin coadministered with OM (32.9 L/h). All adverse events were mild in severity and resolved prior to the end of the study. No serious adverse events or treatment-emergent adverse events led to discontinuation from the study. There was no clinically relevant effect of OM on the pharmacokinetics of metformin in healthy subjects.

Predicting renal clearance of morphine and morphine‐6‐glucuronide using the “organ‐on‐a‐chip” technology and physiologically‐based pharmacokinetic modeling

BackgroundRenal elimination of xenobiotics consists of dynamic sequential and parallel processes including glomerular filtration, active secretion, and active and passive reabsorption. Conventional ways to predict renal clearance involve allometric scaling and in vitro‐to‐in vivo extrapolation using cell lines. However, static predictions using these methods are often not quantitatively accurate because of the differences in transporter expression and function between species and systems, and the lack of dynamics of reabsorption and concentration gradients that exist in the kidney. We hypothesized that a 3D vascularized human proximal tubule microphysiological system (VPT‐MPS) together with physiologically‐based pharmacokinetic (PBPK) modeling could be used to accurately predict human renal clearance. The goal of this study was to test this hypothesis using morphine and its 6‐glucuronide (M6G) as model compounds and to predict their renal clearances from data collected from our VPT‐MPS 1 using our mechanistic kidney PBPK model 2.MethodsHuman proximal tubule epithelial cells (PTECs) collected from three donors were seeded in the 3D VPT‐MPS. Passive diffusion and active secretion clearances of morphine and M6G were measured using the 3D VPT‐MPS in the presence and absence of probenecid (OAT inhibitor) and tetraethyl ammonium (OCT inhibitor). Similarly, passive diffusion and active secretion clearances across PTECs for morphine and M6G were measured in a 2D transwell system. The measured clearances were used with our verified mechanistic kidney PBPK model to predict the renal clearances of morphine and M6G. The predicted renal clearances were compared to the observed in vivo renal clearances to define the accuracy of the predictions.ResultsThe clearances across PTECs in the 3D VPT‐MPS for morphine and M6G were significantly reduced in the presence of probenecid and tetraethyl ammonium. In the 3D VPT‐MPS system, the passive diffusion clearances of morphine and M6G were 0.8 (range: 0.4 – 1.2) and 0.3 (range: 0.2 – 0.7) μL/h, respectively, while the active secretion clearances of morphine and M6G were 2.6 (range: 1.4 – 7.9) and 0.9 (range: 0.04 – 9.3) μL/h, respectively. These results showed a significant active secretion for both morphine and M6G that is mediated by OAT and OCT transporters. The predicted renal clearances using these measured clearances and our mechanistic kidney PBPK model were 7.6 ± 3.0 L/h for morphine and 6.4 ± 1.5 L/h for M6G. These predicted renal clearances were within 2‐fold of the observed population mean renal clearances demonstrating successful in vitro‐to‐in vivo prediction of renal clearance using our method.ConclusionThis study shows that the 3D VPT‐MPS together with mechanistic PBPK modeling can accurately predict renal clearance of drugs that are eliminated through both passive and active processes.Support or Funding InformationNIH UG3TR002158‐02

Disposition of [14C]LY2606368 following intravenous administration in patients with advanced and/or metastatic solid tumours

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours.The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted.The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern.

Abstract C071: Pharmacokinetics and pharmacodynamics of pemigatinib, a potent and selective inhibitor of FGFR 1, 2, and 3, in patients with advanced malignancies

Abstract Pemigatinib is a potent inhibitor of fibroblast growth factor receptors (FGFR) 1, 2, and 3 with selectivity against other kinases and is currently being studied in solid tumors expressing FGFR translocations and/or mutations. A first-in-man phase 1 study (FIGHT-101) was conducted in patients with solid tumors who are refractory to approved treatments, to establish the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of pemigatinib. The study was conducted in 3 parts to allow dose escalation, dose expansion, and food-effect and combination treatments, respectively. Both intermittent (2 wks on/1 wk off) and continuous daily dosing were evaluated. A total of 116 patients have received monotherapy and 44 received combination therapy, as of February 19, 2019. Serial blood samples were collected to enable PK/PD analyses, and plasma samples were assayed for pemigatinib by a validated LC-MS/MS method with a linear validated range of 1 to 1000 nM in human plasma. With multiple-dose administration in the fasted state, pemigatinib plasma concentrations attained peak values (Cmax) typically at 1–2 hours (median Tmax) post-dose, and subsequently exhibited a bi-exponential decay, with a steady-state geometric mean terminal-phase disposition half-life (t½) of approximately 15 hours that was not dose-dependent. The geometric mean accumulation ratio was approximately 1.6 for area under the curve from time 0 to 24 hours (AUC0-24). Within the dose range of 1 to 20 mg once daily (QD), increases in the pemigatinib steady-state Cmax and AUC0-24 were proportional to dose; that is, pemigatinib exhibited linear PK over the dose range studied. Pemigatinib exhibited a low steady-state oral clearance with geometric mean of 9.88–11.7 L/h and moderate volume of distribution with geometric mean of 173–244 L. At the recommended part 2 dose of 13.5 mg QD, the geometric mean (CV%) of t½, steady-state Cmax, and AUC0-24 were 15.4 h (51.6%), 236 nM (56.4%), and 2620 h*nM (54.1%), respectively. The PK parameters of pemigatinib following combination therapy were similar to that of monotherapy. Administration of a standardized high-fat and high-calorie breakfast prolonged the median pemigatinib Tmax to 4 hours, decreased the geometric mean steady-state Cmax by 18%, and increased the geometric mean steady-state AUC0-24 by 11%. The 90% CI of geometric mean ratio for steady-state Cmax and AUC0-24 were (0.648–1.03) and (0.935–1.31), respectively. The effect of food on pemigatinib plasma exposures was considered as modest and not clinically meaningful. Therefore, pemigatinib can be administered without regard to food. The geometric mean fraction of pemigatinib excreted in urine was 1.19% (range, 0.226–7.24%) with a geometric mean renal clearance of 0.133 L/h based on exploratory urine excretion data, indicating minor contribution from renal clearance towards total systemic clearance. Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition. The increase in serum phosphorus observed after treatment with pemigatinib was exposure-dependent and followed a sigmoidal relationship. In conclusion, pemigatinib exhibits rapid absorption, linear PK, and a t½ consistent with QD dosing. Pemigatinib is predominantly cleared by metabolism and there are no active metabolites. Citation Format: Tao Ji, Christine Lihou, Ekaterine Asatiani, Luis Féliz, Heather Overholt, Robert Landman, Xuejun Chen, Swamy Yeleswaram. Pharmacokinetics and pharmacodynamics of pemigatinib, a potent and selective inhibitor of FGFR 1, 2, and 3, in patients with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C071. doi:10.1158/1535-7163.TARG-19-C071

Positive association of residual kidney function with hemoglobin level in patients on peritoneal dialysis independent of endogenous erythropoietin concentration

BackgroundHow residual kidney function (RKF) functions in the prevention of anemia in peritoneal dialysis (PD) patients is unclear. In this study, we investigated the association between RKF and hemoglobin (Hb) level.MethodsWe performed a cross-sectional analysis of the association between RKF, defined as the mean renal creatinine and urea clearance (rCUC), and the Hb level in 50 PD patients registered retrospectively. The independent variable was mean rCUC as continuous or categorical variable by tertile, and the dependent variable was Hb level as continuous or dichotomous variable using Hb cutoff of 10 g/dL. We conducted a multivariable regression analysis and calculated the c-statistic for Hb level < 10 g/dL using a receiver operating characteristic curve.ResultsIn multivariable regression analysis, mean rCUC was significantly associated with Hb level independent of dose of erythropoiesis-stimulating agent (ESA) and endogenous erythropoietin (eEPO) concentration. Multivariable adjusted least square means of the Hb level were higher with increase in the mean rCUC tertile. The c-statistic (95% confidential interval) for a Hb level < 10 g/dL was significantly greater in the model with mean rCUC than without [0.931 (0.789–0.980) vs. 0.856 (0.697–0.939), P = 0.044].ConclusionA decline in RKF is associated with anemia in PD patients independent of ESA dose and eEPO concentration.Trial registrationUMIN000018902

Acetylator Status Impacts Amifampridine Phosphate (Firdapse™) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function

PurposeThe purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes. MethodsThis was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations. FindingsAmifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC0-∞ and Cmax were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC0–∞ was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC0-∞, approximately 1.8-fold; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-∞ from normal to severe RI. No new tolerability findings were observed. ImplicationsA single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60–80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.

ObjectiveDA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects.MethodsA dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated.ResultsAfter a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.ConclusionIn conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20–80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

Evaluation of pharmacokinetic and pharmacodynamic interactions of sodium oxybate with ibuprofen: A randomized, double-blind, placebo-controlled, crossover study

Sodium oxybate (SXB) is the sodium salt of gamma hydroxybutyrate (GHB), a substrate for the monocarboxylate transporter (MCT) that may be inhibited by nonsteroidal anti-inflammatory drugs. This study evaluated potential drug–drug interactions of SXB and ibuprofen with regard to pharmacokinetics (PK), pharmacodynamics (PD), and safety. Healthy volunteers were randomized to SXB + ibuprofen placebo, SXB + ibuprofen, or SXB placebo + ibuprofen in a three-period, double-blind, crossover design with a 2-day washout between periods. Ibuprofen/placebo (4x200mg capsules) was given qid every 4 h on days 1 and 2, and 1 h before and 3 h after the first SXB dose on day 3; SXB/placebo was given as two 3 g doses 4 h apart on day 3. Blood and urine samples were taken at predefined times for noncompartmental PK analysis. PD testing, performed during each treatment period, included the Karolinska Sleepiness Scale (KSS), and a selection of automated tests from CDR System (www.bracketglobal.com) including the Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Tracking, and Numeric Working Memory tasks. Safety was assessed at specified time points, and throughout the study. 21 subjects enrolled and completed the study (95% male; 57% white; mean age 34.4 ± 8.4 years). Although mean plasma SXB concentrations were approximately 5% lower with ibuprofen co-administration ( P < 0.05), the 90% CIs of the geometric LS means for SXB PK parameters with and without ibuprofen were within the 80–125% equivalence range. Urinary excretion of SXB increased ∼2-fold with ibuprofen (mean renal clearance = 874.2 mL/h for SXB + ibuprofen and 463.6 mL/h for SXB alone; P < 0.0001), and the percent mean ratio of the geometric LS means was 194% (90% CI 172%, 219%) exceeding the equivalence range. Cognitive function impairments and increased sleepiness were observed with SXB with and without ibuprofen, but no PD interactions were observed. The most common adverse events (AEs) were consistent with the drug profiles. AEs in ⩾2 subjects with SXB + ibuprofen were somnolence ( n = 15), euphoric mood ( n = 10), dizziness ( n = 5), headache ( n = 3), and nausea ( n = 2), and reflect a combined effect of both drugs. Although renal excretion of SXB increased, likely as a result of MCT inhibition by ibuprofen, plasma PK ratios were within the equivalence range, suggesting the interaction was not clinically significant. No PD interactions were observed, and AEs were consistent with the drug profiles. This study was sponsored by Jazz Pharmaceuticals, Inc.

Oral Prucalopride in Children With Functional Constipation

Prucalopride is a selective, high-affinity 5-HT4 receptor agonist with gastrointestinal prokinetic activities. The aim of this study was to evaluate the pharmacokinetics, efficacy, safety, and tolerability of prucalopride oral solution in children, ages 4 years or older to 12 years or younger, with functional constipation. A single oral dose of 0.03 mg/kg prucalopride was administered to 38 children to characterize prucalopride pharmacokinetics (NCT01674166). Thereafter, 37 children entered an open-label extension period in which 0.01 to 0.03 mg/kg of prucalopride was administered once per day for 8 weeks to investigate efficacy, safety, and tolerability (NCT01670669). Mean (standard deviation [SD]) Cmax, tmax, and AUC∞ (area under the plasma concentration-time curve from time 0 to infinity) were 3.8 (0.6) ng/mL, 1.8 (0.9) hour, and 65.3 (10.6) ng · h · mL, respectively, with limited (16%) variability in Cmax and AUC∞. Mean (SD) t1/2 was 19.0 (3.1) hours. On average, mean (SD) renal clearance (0.25 [0.08] L · h · kg) accounted for 54% of the apparent total plasma clearance (0.46 [0.07] L · h · kg). The apparent volume of distribution was 12.6 (2.6) L/kg. Prucalopride treatment resulted in a mean bowel movement frequency of 6.8/week, normal stool consistency, and reduced frequency of fecal incontinence. During the 8-week extension, 70% of study participants had at least 1 adverse event (all but 1 of mild/moderate intensity, 19% considered related to prucalopride). No children discontinued prucalopride because of adverse events. The pharmacokinetic profile of a single dose of prucalopride oral solution (0.03 mg · kg · day) generally resembled the profile in adults (2-mg tablet) but reflected lower systemic exposure in children. Prucalopride treatment for 8 weeks demonstrated an apparent favorable efficacy and tolerability profile in children with functional constipation.

Performance of Methods to Assess Kidney Function in a Predominantly Overweight Sample of Patients with Liver Disease

The assessment of glomerular filtration rate (GFR) in patients with liver disease is necessary to make decisions about organ allocation. Creatinine is widely used as a marker of GFR; however, it is not reliable in patients with liver disease. The aims of this study were to (1) determine if iodine 125-labeled iothalamate (125I-iothalamate) clearance calculated using the plasma decay method is equal to renal clearance of 125I-iothalamate and (2) estimate kidney function using the creatinine-based Cockcroft–Gault and the Modification of Diet in Renal Disease equations, a cystatin C-based equation, the urine collection method for creatinine clearance, and plasma clearance of vancomycin (V) and compare these estimates to renal clearance of 125I-iothalamate in adult patients with liver disease. Adults with liver disease received 125I-iothalamate and V and had a catheter placed for urine collection. Blood and urine samples were collected over 8 h for analysis of 125I-iothalamate, creatinine, and V to determine kidney function. Estimates were compared to renal 125I-iothalamate clearance. Eight patients classified as Child–Pugh class B were enrolled: age was 52 ± 6 years; body mass index was 36.5 ± 19 kg/m2; and Model for End-Stage Liver Disease score was 13 ± 3. Mean estimates of kidney function did not differ significantly from mean renal 125I-iothalamate clearance (74 ± 38 mL/min/1.73 m2). Other methods overestimated kidney function at lower levels of GFR (<60 mL/min/1.73 m2) and underestimated kidney function at higher GFR levels. Given the variability in performance of methods to assess kidney function in this population, direct measurement of GFR may be preferable to indirect estimates based on marker compounds such as creatinine and cystatin C until more accurate methods are developed.

The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans

The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians. Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg). The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC(0-32 h)) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C(max)) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete. Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.

In Vitro P-Glycoprotein Interactions and Steady-State Pharmacokinetic Interactions Between Tolvaptan and Digoxin in Healthy Subjects

Interactions between tolvaptan and digoxin were determined in an open-label, sequential study where 14 healthy subjects received tolvaptan 60 mg once daily (QD) on days 1 and 12 to 16 and digoxin 0.25 mg QD on days 5 to 16. Mean maximal concentrations (C(max)) and area under the curve during the dosing interval (AUC(τ)) for digoxin with tolvaptan (day 16) were increased 1.27- and 1.18-fold compared with digoxin alone (day 11); mean renal clearance of digoxin was decreased by 59% (P < .05). Tolvaptan C(max) and AUC(0-24h) for a single dose with digoxin (day 12) were each increased about 10% compared with tolvaptan alone (day 1). Tolvaptan did not accumulate upon multiple dosing. After a single dose of tolvaptan (day 1, day 12), 24-hour urine volume was about 7.5 L. As expected, after 5 days of tolvaptan, 24-hour urine volume decreased about 20%. In vitro studies in control and MDR1-expressing LLC-PK1 cells indicate that tolvaptan is a substrate of P-glycoprotein. Tolvaptan (50 µM) inhibited basolateral to apical digoxin secretion to the same extent as 30 µM verapamil; the IC50 of tolvaptan was determined to be 15.9 µM. The increase in steady-state digoxin concentrations is likely mediated by tolvaptan inhibition of digoxin secretion.

Clinical Pharmacokinetics of Metformin

Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(&frac12;)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.

Effects of Sodium Bicarbonate and Ammonium Chloride Pre-treatments on PEPT2 (SLC15A2) Mediated Renal Clearance of Cephalexin in Healthy Subjects

PEPT2 mediates the H(+) gradient-driving reabsorption of di- and tri-peptides, and various peptidomimetic compounds in the kidney. This study examines the influence of urinary pH modification through sodium bicarbonate and ammonium chloride pre-treatments on the function of PEPT2 in healthy subjects, using cephalexin as the probe drug. Sixteen male subjects received a single oral dose of 1000 mg cephalexin under ammonium chloride and sodium bicarbonate treatment, respectively, with a wash-out period of one week. The study subjects were genotyped for PEPT2 polymorphic variants. Cephalexin concentrations in plasma and urine were determined by high performance liquid chromatography. The mean renal clearance of cephalexin was significantly higher under ammonium chloride treatment than that under sodium bicarbonate treatment (P < 0.01). This difference was significant for PEPT2*2/*2 (P = 0.017) but not for PEPT2*1/*1 (P = 0.128). No differences were observed for other pharmacokinetic parameters. The findings of this study suggest that urinary pH changes may alter the pharmacokinetics of PEPT2's substrates. This effect was more obvious for the PEPT2*2/*2.

Elimination Kinetics of the Tobacco-Specific Biomarker and Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is tobacco specific and has a longer half-life than other tobacco biomarkers studied thus far. An accurate measurement of the NNAL half-life is important for optimal use to assess exposure to tobacco smoke. We determined the half-life of NNAL in urine in eight daily smokers on a clinical research ward and in five occasional smokers in a real-life environment. Total NNAL in urine was monitored for 14 days in daily smokers after stopping smoking and for up to 60 days in occasional smokers. The average half-life for the terminal phase in the daily smoker group using a two-compartmental body model was 10.3 days (beta phase), and using a noncompartmental model, it was 9.1 days. In the occasional group, these values were 17.6 and 16.0 days, respectively. The alpha-phase half-lives were 14.3 and 27.8 hours for the two groups, respectively. The inter-subject coefficient of variation of the NNAL terminal half-life ranged from 14% to 30%, and the intra-subject coefficient of variation ranged from 3% to 18%. There was very good agreement between the plasma and urinary half-lives in two subjects with plasma analyses: 7.4 versus 7.9 days and 9.2 versus 10.7 days. Mean renal clearance of NNAL was 13 +/- 2.3 mL/min. The terminal half-life of NNAL of 10 to 18 days indicates that this biomarker can be used to detect tobacco smoke exposure for 6 to 12 weeks after cessation of exposure and requires a similar time to assess the steady levels of NNAL after switching from one tobacco product to another.