Apparent Total Body Clearance Research Articles

Guiding Dyslipidemia Treatment: A Population Pharmacokinetic-Pharmacodynamic Framework for Obicetrapib.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3-compartment model with 4-compartment transit absorption and first-order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. The maximum stimulatory effect of obicetrapib on LDL-C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL-C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL-C and HDL-C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision-making throughout the development lifecycle.

Effects of Resveratrol Co-Administration on Celecoxib Disposition and Pharmacokinetics in Healthy Volunteers

AbstractThe objective of the current study was to investigate the effects of resveratrol (RSV), a natural herbal remedy used as an adjacent anti-inflammatory supplement on, the pharmacokinetics of celecoxib in healthy male volunteers. Twelve healthy human participants were involved in two-period open-labeled trial. Celecoxib (200 mg) was given as a single oral dose under fasting conditions as a control phase. Afterward, RSV (500 mg) commenced as a single oral dose for ten days as a treatment phase. Blood samples were collected during the control and treatment phases and analyzed using the validated High-performance liquid chromatography (HPLC) method. RSV pre-exposure significantly increased the area under the curve (AUC0–24), peak plasma concentration (Cmax), absorption rate constant (ka), and prolongated half-life (t1/2), along with a decrease in elimination rate constant (ke). Meanwhile, the volume of distribution (Vd/F) and apparent total body clearance (CL/F) were significantly decreased for celecoxib. There was no significant change in the time it takes for celecoxib to reach the maximum concentration (tmax) was observed. The obtained results suggested the presence of a beneficial pharmacokinetic interaction between RSV and celecoxib. Consequently, combining resveratrol as an herbal remedy and celecoxib as an anti-inflammatory drug may synergistically reduce inflammation and osteoarthritis with minimal side effects.

Pharmacokinetics and Tolerability of Zibotentan in Patients with Concurrent Moderate Renal and Moderate Hepatic Impairment.

Zibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants. Twelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) and from time zero to the time of the last measurable concentration (AUClast), and maximum plasma drug concentration (Cmax) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge. In total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC∞ and AUClast) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while Cmax and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/F in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/F with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/F in participants with moderate hepatic impairment. The presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment. ClinicalTrials.gov identifier: NCT05112419.

Plasma and tissue kinetics of enrofloxacin and its metabolite, ciprofloxacin, in yellow catfish (Pelteobagrus fulvidraco) after a single oral administration at different temperatures

The objective of this study was to examine the pharmacokinetic (PK) properties of enrofloxacin (EF) and its metabolite, ciprofloxacin (CF), in yellow catfish (Pelteobagrus fulvidraco) after a single oral dose of EF at 20 mg/kg at 20, 25, and 30 °C. Samples were collected at pre-designed time points and determined by high-performance liquid chromatography with a fluorescent detector. Results showed that most concentrations of EF and CF in plasma and tissues at the same time point at different temperatures were statistically significant. With the increase in temperature, the terminal half-life (T1/2λz) of EF and CF was first reduced from 20 to 25 °C but elevated from 25 to 30 °C in plasma, muscle + skin, gill, liver, and kidney, respectively. The area under the plasma concentration-time curves (AUClast) of EF were all decreased in plasma, muscle + skin, and gill except for that of EF in the liver and kidney. However, the AUClast and the apparent metabolic rate of CF were exhibited first elevated and then decreased trend. The apparent volume of distribution (Vz_F) of EF was first reduced from 20 to 25 °C but increased at 30 °C. The apparent total body clearance (CL_F) of EF was increased from 0.15 to 0.32 L/h·kg with the temperature elevation. These indicated that increased temperature markedly affected the PKs of EF and CF in yellow catfish. Through in-depth analysis, the EF dosage of 20 mg/kg is appropriate to use in yellow catfish at 20 and 25 °C but 30 °C.

The plasma and tissue kinetics of sulfadiazine and its metabolite in Ictalurus punctatus after oral gavage at two temperatures.

A plasma and tissue kinetic study of sulfadiazine (SDZ) and its metabolite, N4 -acetyl sulfadiazine (ACT-SDZ), was characterized in channel catfish (Ictalurus punctatus) following a single oral dose of 50 mg/kg at 18 and 24°C. Samples were collected at predetermined time points and determined by ultra-performance liquid chromatography. The classical one-compartmental method was used to estimate the pharmacokinetic parameters. Results showed that the changing of temperature was markedly influential on the kinetics of SDZ and ACT-SDZ in plasma and tissues. When the temperature was increased from 18 to 24°C, the elimination half-life (K10_HF) of SDZ was decreased in gill, kidney, and muscle + skin, but increased in liver and plasma. The K10_HF of ACT-SDZ also had a decreased trend in gill, liver, and plasma but had comparable values in kidney and muscle + skin. The absorption half-life (K01_HF), time to peak concentration (Tmax ), and area under concentration-time curve (AUC0-∞ ) of SDZ and ACT-SDZ all exhibited declined tendencies in plasma and tissues. The apparent volume of distribution (V_F) of SDZ in plasma was increased from 0.53 to 1.48 L/kg, and the apparent systemic total body clearance (Cl_F) was increased from 0.028 to 0.060 L/h/kg. In a word, K01_HF, Tmax , and AUC0-∞ of SDZ and ACT-SDZ were decreased in plasma and tissues with the increase of temperature, whereas the V_F and Cl_F of SDZ were increased. Meanwhile, we calculated the percentage of time profile of SDZ concentration more than minimum inhibitory concentration to total time (%T > MIC) to guide clinical usage of SDZ. When the dosage interval was 24 h, the values of %T > MIC were all >90% in plasma and most tissues. Therefore, we recommend an oral dose of SDZ at 50 mg/kg once per 24 h at 18-24°C against the fish pathogens with an MIC value of ≤6.4μg/mL.

Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [Cmax], area under the curve [AUC]inf and AUClast) and secondary PK parameters (AUC0-t, apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [Tmax], and half-life [T1/2]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non‑compartmental analysis. Cmax of alpelisib decreased by approximately 17% in the moderate hepatic impairment group vs. the healthy control group (geometric mean ratio; GMR [90% confidence interval; CI], 0.833 [0.530, 1.31]). Cmax in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUClast for alpelisib decreased by approximately 27% in the moderate hepatic impairment group vs. the healthy control group (GMR [90% CI], 0.726 [0.487, 1.08]). AUClast was 26% higher in the severe hepatic impairment group compared with the healthy control group (GMR [90% CI], 1.26 [0.845, 1.87]). Overall, 3 participants (13.0%) experienced at least 1 adverse event which were either grade 1 or 2. Adverse events did not lead to study drug discontinuation. No grade 3 or 4 adverse events, serious adverse events or deaths were reported. The results indicate that a single dose of alpelisib was well tolerated in this study population. There was no significant impact of moderate or severe hepatic impairment on the exposure of alpelisib.

Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide.

Background and ObjectiveTirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function.MethodsParticipants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration–time curve from zero to infinity (AUC0–∞) and maximum observed drug concentration (Cmax) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability.ResultsTirzepatide exposure, based on AUC0–∞ and Cmax, was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC0–∞ or Cmax between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC0–∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and Cmax ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to Cmax of tirzepatide across all groups (time to Cmax median difference vs control [90% CI]: 0 [− 4.00, 12.00], 0 [− 12.00, 12.00], and 0 [− 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC0–∞, Cmax, and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants.ConclusionsTirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments.Clinical Trial RegistrationClinicalTrials.gov identifier number NCT03940742.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01140-3.

Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment.

ABSTRACTTebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).

Comparative Pharmacokinetics of Sulfadiazine and Its Metabolite N4-Acetyl Sulfadiazine in Grass Carp (Ctenopharyngodon idella) at Different Temperatures after Oral Administration.

In this study, the plasma pharmacokinetics and tissue disposition of sulfadiazine (SDZ) and its main metabolite, N4-acetyl sulfadiazine (ACT-SDZ), were compared between 18 and 24 °C following a single oral administration of SDZ at 50 mg/kg in grass carp (Ctenopharyngodon idella). The plasma and tissues were sampled from 0.167 h up to 96 h and analyzed by ultra-performance liquid chromatography with an ultraviolet detector. The pharmacokinetic parameters were estimated using a one-compartmental approach. Results showed that pharmacokinetics of SDZ and ACT-SDZ in plasma and tissues were notably influenced by the increase of temperature. The increased temperature shortened the absorption half-life (K01_HL) of SDZ and ACT-SDZ in gill, kidney, and plasma, but increased in liver and muscle + skin. The elimination half-life (K10_HF) and the area under concentration-time curve (AUC0–∞) of SDZ and ACT-SDZ all presented a declined trend. The apparent volume of distribution (V_F) of SDZ in plasma was increased from 0.93 to 1.64 L/kg, and the apparent systemic total body clearance (Cl_F) was also increased from 0.01 to 0.05 L/h/kg. Overall, the rise of temperature decreased K10_HF, AUC0–∞ of SDZ, and ACT-SDZ in plasma and tissues, but increased V_F and Cl_F in the plasma for SDZ.

Multiple-Ascending-Dose Study of the Soluble Guanylate Cyclase Stimulator, IW-1701, in Healthy Subjects

▪Background: Nitric oxide (NO), a key regulator of vascular health, modulates smooth muscle tone and blood pressure, inhibits vascular smooth muscle proliferation, and suppresses inflammation and platelet activation. These protective functions are mediated by soluble guanylate cyclase (sGC), a signaling enzyme that catalyzes the formation of cyclic guanosine monophosphate (cGMP) in response to NO binding. The compromised vascular health characteristic of the hemoglobinopathies may in part be due to deficient NO bioavailability and inadequate sGC-cGMP signaling. IW-1701 is an orally available sGC stimulator that binds to sGC and enhances NO-sGC-cGMP signaling.Methods: A Phase 1b placebo-controlled, randomized, multiple-ascending-dose study was conducted to assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (blood pressure, heart rate, platelet function, and plasma cGMP) of IW-1701 in healthy subjects. Five successive cohorts of 11 subjects each (8 active and 3 placebo) were randomized. The first 3 cohorts received 7 days of repeated once-daily (QD) doses of 1-, 2- or 5-mg IW-1701 respectively, and the last 2 cohorts received 7 days of lead-in QD doses of 3 mg followed by 7 days of up-titrated QD doses of 5 or 6 mg, respectively.Results: IW-1701 doses ranging from 1 to 6 mg were tolerated and no safety concerns were identified. There were no serious adverse events (SAEs), severe adverse events (AEs), or withdrawals due to AEs. All AEs were mild or moderate, most resolved on the day of onset. Among the 40 subjects who received IW-1701 for 7 consecutive days, the most common AEs were tachycardia and headache (each reported in 7 subjects), and hypotension and nausea (each reported in 3 subjects). Among the 16 subjects who received an up-titrated dose of IW-1701 for 7 additional days, headache was the only AE reported in >1 subject (2 subjects). IW-1701 was rapidly absorbed, with median Tmax achieved from 2 to 4 hours postdose. Systemic exposure to IW-1701 was less than dose proportional after a single dose (Cmax slope, 0.701 [90% CI, 0.578-0.824] and AUCtau slope, 0.833 [90% CI, 0.726-0.939]) and was dose proportional after 7 days of QD dosing (Cmax slope, 1.01 [90% CI, 0.873-1.14] and AUCtau slope, 1.03 [90% CI, 0.892-1.17]). Intersubject variability in PK was low to moderate (AUCtau %CV range, 10.6-39.1%). The accumulation ratio (based on RAUC) ranged from 1.95 to 2.63 across doses of 1-, 2-, 3-, and 5-mg IW-1701 after 7 days of QD dosing. Mean CL/F (apparent total body clearance) and Vz/F (apparent volume of distribution) ranged from 1080 to 1520 mL/h and 49.4 to 58.9 L, respectively. Mean terminal t1/2 was 30 hours, which is consistent with a QD dosing regimen. After 7 days of QD dosing, least squares mean changes from baseline in 24-hour ambulatory systolic blood pressure (±SE) (in cohort order) were -1.17±1.24 (placebo), -2.98±1.80 (1 mg), -5.37±1.71 (2 mg), -6.67±1.69 (5 mg), -6.55±1.95 (3 mg), and -4.98±1.68 mmHg (3 mg). After 14 days of QD dosing in the 2 cohorts that received up-titrated doses, the least squares mean changes from baseline in 24-hour ambulatory systolic blood pressure (±SE) were -1.51±2.42 (placebo), -6.85±2.03 (5 mg), and -8.64±2.08 mmHg (6 mg). Plasma cGMP levels were highly variable; in general, mean plasma cGMP levels were increased from baseline at dose levels ≥3 mg IW-1701. There were no clinically meaningful changes from baseline in platelet function assessment by PFA-100® at any dose level.Conclusion: IW-1701 was tolerated in healthy subjects with only mild and moderate AEs. Common AEs were consistent with the effects of sGC stimulation. Lead-in dosing with a lower dose (3 mg) appeared to improve the tolerability of higher doses (5 and 6 mg). The PK of repeat IW-1701 dosing was dose proportional with low-to-moderate intersubject variability and half-life consistent with QD dosing. Pharmacodynamic results, including blood pressure and plasma cGMP levels, demonstrated target engagement. Clinical evaluation of IW-1701 in diseases associated with NO deficiency, including sickle cell disease and achalasia, are planned or ongoing.– The authors gratefully acknowledge the early contributions of Bernard J. Lavins. – DisclosuresMittleman:Ironwood Pharmaceuticals: Employment, Equity Ownership. Wilson:Ironwood Pharmaceuticals: Employment, Equity Ownership. Sykes:Ironwood Pharmaceuticals: Employment, Equity Ownership. Mihova:Ironwood Pharmaceuticals: Employment, Equity Ownership. Chickering:Ironwood Pharmaceuticals: Employment, Equity Ownership. Hall:Ironwood Pharmaceuticals: Employment, Equity Ownership. Milne:Ironwood Pharmaceuticals: Employment, Equity Ownership. Currie:Ironwood Pharmaceuticals: Employment, Equity Ownership. Chien:Ironwood Pharmaceuticals: Employment, Equity Ownership.

Intravenous Vipera berus Venom-Specific Fab Fragments and Intramuscular Vipera ammodytes Venom-Specific F(ab')2 Fragments in Vipera ammodytes-Envenomed Patients.

Vipera ammodytes (V. ammodytes) is the most venomous European viper. The aim of this study was to compare the clinical efficacy and pharmacokinetic values of intravenous Vipera berus venom-specific (paraspecific) Fab fragments (ViperaTAb) and intramuscular V. ammodytes venom-specific F(ab’)2 fragments (European viper venom antiserum, also called “Zagreb” antivenom) in V. ammodytes-envenomed patients. This was a prospective study of V. ammodytes-envenomed patients that were treated intravenously with ViperaTAb or intramuscularly with European viper venom antiserum that was feasible only due to the unique situation of an antivenom shortage. The highest venom concentration, survival, length of hospital stay and adverse reactions did not differ between the groups. Patients treated with intravenous Fab fragments were sicker, with significantly more rhabdomyolysis and neurotoxicity. The kinetics of Fab fragments after one or more intravenous applications matched better with the venom concentration in the early phase of envenomation compared to F(ab’)2 fragments that were given intramuscularly only on admission. F(ab’)2 fragments given intramuscularly had 25-fold longer apparent total body clearance and 14-fold longer elimination half-time compared to Fab fragments given intravenously (2 weeks vs. 24 h, respectively). In V. ammodytes-envenomed patients, the intramuscular use of specific F(ab’)2 fragments resulted in a slow rise of antivenom serum concentration that demanded their early administration but without the need for additional doses for complete resolution of all clinical signs of envenomation. Intravenous use of paraspecific Fab fragments resulted in the immediate rise of antivenom serum concentration that enabled their use according to the clinical progress, but multiple doses might be needed for efficient therapy of thrombocytopenia due to venom recurrence, while the progression of rhabdomyolysis and neurotoxic effects of the venom could not be prevented.

Population pharmacokinetic and exposure-response analyses of d-amphetamine after administration of lisdexamfetamine dimesylate in Japanese pediatric ADHD patients

Lisdexamfetamine dimesylate, a prodrug of d-amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d-amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d-amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index. A total of 1365 points of plasma d-amphetamine concentrations from pediatric patients (6–17 years) with ADHD in clinical studies conducted in Japan and the US were employed for the population pharmacokinetic analysis. The plasma concentrations of d-amphetamine in pediatric patients with ADHD were well described by a one-compartment model with first-order absorption and lag time. The effects of body weight and ethnicity (Japanese or non-Japanese) on apparent total body clearance and the effect of body weight on apparent volume of distribution were incorporated into the final model. No clear exposure-dependent reduction was evident from the ADHD RS-IV total score, whereas the reductions were greater for the lisdexamfetamine dimesylate treatment groups compared with the placebo group regardless of exposure to d-amphetamine.

Pharmacokinetic Herb‐Drug Interaction between Hibiscus sabdariffa Calyces Aqueous Extract and Captopril in Rats

Hibiscus sabdariffa L. (Malvaceae) is a traditional medicinal herb widely consumed as a beverage (“hibiscus tea”), and its global popularity is expanding due to health benefits such as blood pressure and cholesterol control. Previous studies showed that Hibiscus sabdariffa is coadministered with antihypertensives and antihyperlipidemics, thus predisposing herb-drug interactions. We investigated the pharmacokinetic interaction between H. sabdariffa L. aqueous extract and captopril, a frequently prescribed antihypertensive. In this study, chemical profile of H. sabdariffa L. aqueous extract was identified using HPLC system equipped with a DAD detector at 360 nm and 520 nm. The male Sprague Dawley rats were divided into two groups of six rats. Group I received a single dose of captopril suspension (4.5 mg/200 g body weight (BW) orally (p.o.)) while group II received H. sabdariffa L. aqueous extract (60 mg/200 g BW; p.o.) daily for two weeks prior to the same captopril dose. Multiple blood samples were collected at predetermined times after captopril administration and the plasma concentration was analyzed using ultrahigh-pressure liquid chromatography-tandem mass spectrometry. Chemical profiling of the H. sabdariffa L. aqueous extract showed that the extract contains chlorogenic acid, myricetin 3-arabinogalactoside, 5-O-caffeoylshikimic acid, quercetin 3-rutinoside, delphinidin 3-sambubioside, and cyanidin 3-sambubioside. Ingestion of the extract significantly reduced the captopril area under the curve (AUC)0−t (0.1745 (0.1254–0.2429)), AUC0−∞ (0.1734 (0.1232–0.2442))], and peak plasma concentration (0.2119 (0.1337–0.3359)) (geometric mean ratio of the coadministration group to the captopril group (90% CI)). The geometric mean ratios were falling outside the 90% CI of 0.8–1.25 bioequivalent range. Conversely, H. sabdariffa L. extract increased the apparent total body clearance (Cl/F, 0.0257 ± 0.0115 vs. 0.1418 ± 0.0338 mL/h·kg) and the apparent volume of distribution (Vd/F, 0.0541 ± 0.0226 vs. 0.3205 ± 0.0790 mL/kg). This study indicated that coadministration of H. sabdariffa L. aqueous extract could change the pharmacokinetic profile of captopril; therefore, its coadministration should be avoided.

Population pharmacokinetic and exposure-response analyses of guanfacine in Japanese pediatric ADHD patients

Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6–17 years obtained from clinical studies in Japan and the US. In addition, the relationship of the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score with exposure to guanfacine was assessed for Japanese pediatric ADHD patients. A one-compartment model with first-order absorption and lag time well described the plasma concentration data of guanfacine in pediatric ADHD patients. Body weight was selected as a covariate of apparent total body clearance and apparent volume of distribution. There was no pharmacokinetic difference between Japanese and non-Japanese pediatric ADHD patients. The results suggested a tendency of exposure-dependent reduction in the ADHD RS-IV total score, whereas the reduction was observed even at low plasma exposure levels compared with the placebo group.

Tacrolimus Pharmacokinetics in Living-Donor and Deceased-Donor Liver Transplant in Saudi Patients

Introduction: Tacrolimus is a macrolide immunosuppressant. It has a narrow therapeutic index and serious side effects which necessitate monitoring of tacrolimus blood concentration. The trough concentration of the drug may also differ based on the type of liver transplant. This study was conducted to investigate differences in pharmacokinetics between transplant types and to determine tacrolimus population pharmacokinetic in liver transplant recipients in Saudi Arabia.
 Method: Patients on tacrolimus, as the main immunosuppressant, who underwent liver transplant throughout2012-2014 were retrospectively studied. Demographic characteristic, tacrolimus blood trough concentrations, liver, renal, biochemistry, and hematology lab results were all collected. The pharmacokinetic parameters were estimated assuming one compartment model.
 Results: Tacrolimus pharmacokinetic parameters were found to be as following; elimination rate constant () 0.094 ± 0.0123, apparent volume of distribution () 112.48±63.033 L/hr, elimination half-life () 7.46± 1.01 hr and apparent total body clearance () 10.27± 5.69 L/hr (mean ± SD).
 Statistically significant difference was found between living-donor and deceased-donor liver transplant with respect to apparent clearance and apparent volume of distribution. Living-donor liver transplant recipients have apparent volume of distribution of 97.39±47.00 L (mean ± SD) and an apparent clearance of 8.89±4.24L/hr (mean± SD). On the other hand, deceased-donor liver transplant has an apparent clearance of 12.97±7.09L/hr (mean ± SD) and an apparent volume of distribution of 142.17± 78.65 L (mean ± SD).
 Conclusions: Tacrolimus pharmacokinetics parameters were accurately determined in liver transplant recipients in Saudi Arabia. The results of the present study can be clinically used in the therapeutic drug monitoring of tacrolimus in the individualization of drug dosage and taking the appropriate clinical decisions to prevent allograft rejection.

Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients.

Mizoribine (MZR) is an immunosuppressive agent with extensive inter-individual differences in pharmacokinetics (PK). Here, we investigated the PK characteristics of MZR in renal transplant recipients and gave equations for prediction of some critical PK parameters. A total of 40 renal transplant recipients participated in this prospective study and were administered MZR orally twice daily in the range of 1.1-8.9mgkg-1day-1. Steady-state concentrations of MZR were detected before (0h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12h after administration by high-performance liquid chromatography method. Another 38 patients with newly detected trough concentration (C0) were enrolled to validate the obtained C0 predictive equation. Significant inter-individual differences in MZR PK parameters were observed. Patients with decreasing creatinine clearance rate (CCr) had significantly decreased terminal elimination rate constant (kel) and apparent total body clearance (Cl/F), while other PK parameters including apparent terminal half-life (t1/2), peak time (Tmax), peak concentration (Cmax), area under the curve (AUC0-12h), apparent volume of distribution (V/F), and mean residence time (MRT) were significantly increased. Correlation coefficients between AUC0-12h and C0/Cmax were 0.894 and 0.916, respectively (both p < 0.001). A serum creatinine (SCr)-based predictive C0 equation [C0 = (2.160 × SCr - 54.473) × Dose] was established and validated by C0 from another 38 patients. Besides, significant linear correlations between kel/t1/2 and CCr were also found (r2 = 0.668 and 0.484, respectively), and equations predicting kel/t1/2 were also obtained (kel = 0.015 + 0.002 × CCr, t1/2 = 13.601 - 0.139 × CCr). Renal function plays as an essential factor that contributes to great inter-individual MZR PK variation. Both C0 and Cmax are suitable for evaluating MZR exposure in the body. SCr could be applied to predict C0 and t1/2 of MZR.

Pharmacokinetics and Safety of DS-8500a, an Antidiabetic Drug, in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center, Open-Label, Single-Dose Study.

The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a. This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety. The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration-time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (Cmax) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to Cmax were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups. DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD. Japic CTI-No. 163135. Daiichi Sankyo Co. Ltd., Tokyo, Japan.

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment.

Mirogabalin (DS‐5565) is a novel preferentially selective α2δ‐1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open‐label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end‐stage renal disease (ESRD)]) were enrolled and completed the study. The AUClast increased with severity of renal impairment; the geometric least‐squares mean ratios of AUClast compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUClast increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment‐related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.

Population Pharmacokinetic and Exposure-Response Analysis of Weekly Teriparatide in Osteoporosis Patients.

Teriparatide is a potent therapeutic agent for the treatment of osteoporosis. One of the aims of this analysis was to develop a population pharmacokinetic (PPK) model to understand the pharmacokinetic characteristics of the once-weekly formulation of teriparatide. Another aim was to develop an exposure-response model to describe the relationship between change in bone mineral density (BMD) and teriparatide exposure after weekly subcutaneous administration. The PPK analysis showed that apparent total body clearance was significantly influenced by estimated creatinine clearance and the presence of osteoporosis. A data set consisting of lumbar spine BMD values for 513 osteoporosis patients whose area under the concentration-time curve (AUC) of teriparatide acetate was estimated by the developed PPK model was then compiled. Exposure-response analysis showed that the percentage change from baseline of BMD was well described by a function of the AUC of teriparatide acetate, time, and coadministration of alfacalcidol and a calcium preparation. The analysis indicated that AUC is an important parameter for predicting BMD response to once-weekly teriparatide in osteoporosis patients.

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At Tmax, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.