Mean Oral Clearance Research Articles

The Effect of Oral Care Foams and a Spray on Salivary pH Changes after Exposure to Acidic Beverages in Young Adults.

Soft drinks may have a deleterious effect on dental health due to a high titratable acidity and a low pH that could be sufficient to induce tooth demineralization. The use of oral care products immediately after acidic challenge may diminish the erosive potential of soft drinks. We assessed the effect of oral care foams and a spray on salivary pH changes after exposure to Coca-Cola® in young adults. Thirty-three consenting eligible patients were recruited in this double-blind, randomized, crossover study performed in six visits. Baseline examination included unstimulated salivary flow rate, stimulated salivary buffer capacity, and the simplified oral hygiene index (OHI-S) assessment. Salivary pH and time for pH recovery were registered after exposure to Coca-Cola® alone or that followed by the application of each of the studied products (an oral foam containing hydroxyapatite and probiotics, an oral foam containing amino fluoride, an alkaline oral spray, and tap water). Thirty-two patients completed the entire study protocol and were included in the final analysis. The mean minimum salivary pH and the mean oral clearance rate after rinsing with Coca-Cola® were 6.3 and 27 min, respectively. Further rinsing with any one of the tested solutions, including tap water, resulted in a significant improvement in these parameters. When the pH curves were plotted, the oral care products demonstrated a lower area under the curve that differed significantly from the area under the curve for Coca-Cola®; tap water did not differ significantly from Coca-Cola® and oral care products. Minimum salivary pH correlated positively with salivary buffer capacity and salivation rate, while salivary clearance correlated with OHI-S plaque scores. In conclusion, the effect of oral care foams and a spray on minimum salivary pH and salivary clearance after exposure to Coca-Cola® did not differ significantly among the tested products and tap water. Trial registration NCT06148662. Funding: none.

Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease

IntroductionWe report pharmacokinetics of oral ruxolitinib in children with steroid refractory acute graft versus host disease (GVHD) (<12y) and chronic GVHD (≤18y) using our published pediatric dosing. MethodsPK sampling before and +2 hours after ruxolitinib was performed in patients with established chronic GVHD. More extensive PK analysis was evaluated in patients with newly diagnosed acute or chronic GVHD before, +0.5, 1, 2, 4 and 6 hours after ruxolitinib in patients >10kg, and before, +3 and +6 hours in children <10kg. We measured pSTAT1, 3 and 5 expression on CD4+ and CD8+ T-cells before and 2 hours after ruxolitinib as a pharmacodynamic marker of JAK/STAT inhibition. ResultsThirteen patients were prospectively enrolled (0-≤18y with existing chronic GVHD(n=8), 0-<12y with new onset steroid refractory acute GVHD(n=4) and newly diagnosed steroid-refractory chronic GVHD(n=1). A large variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (±SD 4.4; range: 3.1-15.3). The average elimination half-life was 2.32 hours (±SD 1.0). Ruxolitinib clearance was higher in children <2 years versus >2 years (12.1 ± 3.0, vs 5.7 ± 2.8 L/h, p=0.005) and was reduced with concurrent azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T-cells at time of peak ruxolitinib absorption (2 hours after dose). ConclusionsChildren<10 kg have lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variabilities in dosing methods leading to decreased drug absorption.

Metabolic, genetic, and pharmacokinetic parameters for the prediction of olanzapine efficacy

Clinical use of the a olanzapine has significantly different individual-to-individual outcomes. Accordingly, this study aimed to develop a means of predicting response to olanzapine using a combined approach based on pharmacokinetics, pharmacometabonomics, and genetic polymorphism. The olanzapine pharmacokinetics of 19 healthy volunteers treated with orally disintegrating tablets were determined using high-performance liquid chromatography–tandem mass spectrometry. Metabolic profiling and phenotyping were performed on the blood samples that remained after pharmacokinetic analysis using ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry. Uridine diphosphate-glucuronosyltransferase (UGT), tyrosine hydroxylase (TH), γ-aminobutyric acid transaminase (GABA-T), and succinic semialdehyde dehydrogenase (SSADH) were identified as key genes. The single nucleotide polymorphism genotypes most related to drug metabolism were investigated by polymerase chain reaction and Sanger sequencing. Forty-one metabolites (p < 0.05) are increased or decreased after treatment with olanzapine. Tryptophan metabolism, norepinephrine metabolism, and γ-aminobutyric acid metabolism were identified as being related to the effects of olanzapine. Subjects carrying rs1641031 AC and CC exhibited a 59.2% increase in the mean peak concentration (Cmax) value and a 25.33% decrease in the mean oral clearance rate (CL/F) value, compared to that in subjects with the GABA-T rs1641031 AA genotype (p < 0.05). Moreover, polymorphism of the GABA-T gene has an impact on the metabolism of 5-hydroxytryptamine. Lysophosphatidylethanolamine (0:0/18:3), lysophosphatidylethanolamine (0:0/22:5), and octadecatrienoic acid distinguish subjects with high and low olanzapine drug oral clearance and are thus identified as biomarkers for predicting its efficacy.

†Pharmacokinetics, Pharmacodynamics, and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese, and White subjects

Lead Author's Financial Disclosures Benny M. Amore is a current employee of Esperion Therapeutics, Inc., and may own Esperion stock and/or stock options. Study Funding Esperion Therapeutics, Inc. Background/Synopsis Bempedoic acid (BA) is an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration. Objective/Purpose To investigate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of BA, in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US. Methods This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70−190 mg/dL; not receiving a statin) after daily BA 180mg dosing for 14 days. Results Enrolled subjects (28% female) ranged 23 - 59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (Vz/F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and Vz/F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was −29% (14) for Japanese subjects, −39% (8) for Chinese subjects, and −17% (28) for White subjects compared with +17% (21) for subjects receiving placebo. Conclusions Results from this study suggest that administration of BA 180mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and Vz/F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA. Benny M. Amore is a current employee of Esperion Therapeutics, Inc., and may own Esperion stock and/or stock options.

Abstract 9741: Pharmacokinetics, Pharmacodynamics and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese and White Subjects

This study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of bempedoic acid (BA), an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US. This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180 mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70–190 mg/dL; not receiving a statin) after daily BA 180-mg dosing for 14 days. Enrolled subjects (28% female) ranged 23-59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180 mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (V z /F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and V z /F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was –29% (14) for Japanese subjects, –39% (8) for Chinese subjects, and –17% (28) for White subjects compared with +17% (21) for subjects receiving placebo. Results from this study suggest that administration of BA 180 mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and V z /F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA.

Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers

PurposeGlasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed.MethodsOpen-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis.ResultsAll 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142–295%) and 137% (97–193%) in the moderate group, and 202% (146–281%) and 120% (77–188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related.ConclusionThe similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment.Trial registration: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).

PHARMACOKINETICS OF RIFABUTIN IN COMBINATION WITH LOPINAVIR-RITONAVIR IN ADULT PATIENTS WITH HIV AND TUBERCULOSIS CO-INFECTION IN BURKINA FASO

BackgroundThis study aimed to assess the pharmacokinetic profile of rifabutin (RBT) given at 150 mg or 300 mg every other day (EOD) in tuberculosis (TB)-HIV co-infected adult patients.MethodsThis is a...

Population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers.

Background Artemisinin-based combination therapy is recommended as first-line anti-malarial treatment worldwide. A combination of artemisinin with the long acting drug piperaquine has shown high efficacy and tolerability in patients with uncomplicated Plasmodium falciparum infections. The aim of this study was to characterize the population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers after two different dose sizes, formulations and in a combination with piperaquine. A secondary aim was to compare two different methods for the evaluation of bioequivalence of the formulations.MethodsFifteen subjects received four different dose regimens of a single dose of artemisinin as a conventional formulation (160 and 500 mg) and as a micronized test formulation (160 mg alone and in combination with piperaquine phosphate, 360 mg) with a washout period of 3 weeks between each period (i.e. four-way cross-over). Venous plasma samples were collected frequently up to 12 h after dose in each period. Artemisinin was quantified in plasma using liquid chromatography coupled with tandem mass spectrometry. A nonlinear mixed-effects modelling approach was utilized to evaluate the population pharmacokinetic properties of the drug and to investigate the clinical impact of different formulations.ResultsThe plasma concentration–time profiles for artemisinin were adequately described by a transit-absorption model with a one-compartment disposition, in all four sequences simultaneously. The mean oral clearance, volume of distribution and terminal elimination half-life was 417 L/h, 1210 L and 1.93 h, respectively. Influence of formulation, dose and possible interaction of piperaquine was evaluated as categorical covariates in full covariate approaches. No clinically significant differences between formulations were shown which was in accordance with the previous results using a non-compartmental bioequivalence approach.ConclusionsThis is the first population pharmacokinetic characterization of artemisinin in healthy volunteers. Increasing the dose resulted in a significant increase in the mean transit-time but the micronized formulation or concomitant piperaquine administration did not affect the pharmacokinetic properties of artemisinin. The results from the traditional bioequivalence evaluation were comparable with results obtained from mixed-effects modelling.

Abstract A135: Physiologically-based pharmacokinetic modeling to support clinical investigation of the EZH2 inhibitor, tazemetostat (EPZ-6438) in INI1-deficient pediatric tumors

Abstract Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2, which has been implicated in the pathogenesis of a variety of malignancies, including B-cell non-Hodgkin lymphoma and INI1-deficient tumors. INI1-negative malignant rhabdoid tumors, for instance, occur mainly in young children. Tazemetostat pharmacokinetic (PK) data from the first in human phase I clinical study (CT.gov: NCT01897571), across the dose range of 100 mg (suspension) and 100, 200, 400, 800 and 1600 mg (tablet) p.o. twice daily (BID), together with in vitro data including plasma protein binding, blood partitioning, metabolic stability and P450 phenotyping were used to simulate adult exposures by physiologically-based PK (PBPK) modeling (GastroPlus™ 8.5, Simulations Plus, Inc.). A model fit of the adult exposures (n = 24) that, based on visual inspection, adequately described the time-concentration profiles of tazemetostat resulted in prediction of mean steady-state AUC0-t and oral clearance (CL/F) within ±30% of the observed results across the dose range. In addition, mean steady-state Cmax were predicted ≤2-fold of the observed values, for both suspension and tablet formulations. The resultant model was then used to simulate tazemetostat steady-state exposures in discrete pediatric age ranges (6 month to 1 year (yr), &amp;gt;1-2 yrs, &amp;gt;2-6 yrs, &amp;gt;6-12 yrs, &amp;gt;12-18 yrs) following BID administration of an oral suspension. In addition to pediatric physiology, the simulations accounted for ontogeny in hematocrit, plasma protein levels and CYP expression. Using this exposure-based analysis, pediatric doses which afforded the target AUC (80% of adult steady-state AUC0-t at 800 mg or 390 mg/m2 BID) were identified. On a body surface area normalized basis, the projected doses were comparable across the age range (1 to 18 yrs), from 270 to 305 mg/m2 BID, with a slightly lower projected dose of 230 mg/m2BID, for the 6 month to 1 yr old group. As the projected doses by age were comparable, population simulations were performed to determine the corresponding exposures for each age range, at a fixed 300 mg/m2 BID dose. At this dose, mean steady-state AUC0-t values ranged from approximately 80% to 100% of that observed in adults at 800 mg BID. Mean steady-state Cmax was projected to range between 895 and 1550 ng/mL (110% to 190% of Cmax,ss at 800 mg BID in adult), but within the safe and efficacious exposure range defined in adult at doses up to 1600 mg BID. This study demonstrates the prospective application of PBPK early in clinical development to support clinical trial design in special populations, and has provided dosing recommendations for future tazemetostat trials in pediatric patients, ages 6 months to 18 years. Citation Format: Nathalie Rioux, Heike Keilhack, Blythe Thomson, Richard Chesworth, Robert A. Copeland, Eric Hedrick, Peter Ho, Nigel J. Waters. Physiologically-based pharmacokinetic modeling to support clinical investigation of the EZH2 inhibitor, tazemetostat (EPZ-6438) in INI1-deficient pediatric tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A135.

Effect of peginterferon alfa‐2a (40KD) on cytochrome P450 isoenzyme activity

Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to down-regulate hepatic cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and clearance, there is a need to investigate the effect of peginterferon (PEG-IFN) alfa-2a (40KD) on the activity of these enzymes in vivo. Fourteen healthy, male volunteers aged 18 to 45 years were recruited into an open label, two period, single centre study in which CYP enzyme activity was measured by administration of the selectively metabolized probe drugs theophylline (CYP1A2), tolbutamide (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6) and dapsone (CYP3A4) on day 1 of the study. PEG-IFN alfa-2a (40KD) 180 μg was given subcutaneously each week from day 15 to 36, and probe drugs were re-administered on day 37. Probe drugs and metabolites were quantified in plasma or urine samples and used to derive pharmacokinetic parameters. PEG-IFN alfa-2a (40KD) significantly increased the area under the serum drug concentration vs. time curve (AUC(0,∞)) for theophylline by 24%, with a reduction in the mean oral clearance of theophylline of 20%. There were no effects on the pharmacokinetics of any of the other probe drugs. The incidence of adverse events was as expected in subjects receiving pegylated interferon. These results suggest there may be an inhibitory effect of PEG-IFN alfa-2a (40KD) on CYP1A2. PEG-IFN alfa-2a (40KD) had no effect on CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in healthy subjects.

Pharmacokinetics of Tacrolimus During Pregnancy

Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. Blood, plasma, and urine samples were collected over 1 steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. A mixed-effect linear model was used for comparison across gestational age and using postpartum as the reference group. The mean oral clearance (CL/F) based on whole-blood tacrolimus concentration was 39% higher during mid-pregnancy and late pregnancy compared with postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus-free fraction increased by 91% in plasma (f(P)) and by 100% in blood (f(B)) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = -0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy-related changes in f(P) and f(B) contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r² = 0.36 and 0.47, respectively, P < 0.01). In addition, tacrolimus whole-blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% to maintain tacrolimus whole-blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound area under the concentration-time curve, by 112% and 173%, respectively, during pregnancy (P = 0.02 and 0.03, respectively). Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole-blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.

Exposure-Clinical Response Analysis of Paricalcitol in Patients With Chronic Kidney Disease (Stage 5) on Hemodialysis or Peritoneal Dialysis

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.

Phase I study of OPB51602, a small molecule inhibitor of STAT3 phosphorylation, in patients with refractory solid malignancies.

3002 Background: STAT3 is constitutively activated by growth signaling pathways in many malignancies; in many cell lines inhibition of STAT3 leads to cell death. OPB51602 is a small molecule inhibitor of STAT3 phosphorylation (Tyr705) and activation. Methods: A phase I study of OPB51602 administered for 2 weeks every 3 weeks was initiated to determine the maximum tolerable dose (MTD), evaluate pharmacokinetics (PK), and assess pharmacodynamics effects on STAT3 in peripheral blood mononuclear cells (PBMCs). The starting dose was 2mg/day, and dose escalations to 5mg/d, 10mg/d, 20mg/d, were planned. Single dose PK was done on the first day of administration for 4 days. Dose escalation was based on the “3+3” design, MTD was defined as the dose with at least 2/6 dose limiting toxicities (DLTs) in the first cycle and toxicities were graded by NCICTCv4.0. Results: 32 patients (pt) were treated at doses of 2mg/d (n=7), 4mg/d (n=18), 5mg/d (n=7). The main toxicities observed included nausea/vomiting, diarrhea, peripheral neuropathy and fatigue. 5 mg/d was the MTD, where cycle 1 DLTs of grade 3 diarrhea/dehydration and hyponatremia occurred in 1 patient respectively. One pt developed grade 3 peripheral neuropathy at 4mg/d cohort. PK showed maximal drug levels 2-3 hours after administration, bi-exponential decay, with mean oral clearance of 316.5 +/- 638.9 L/h and long terminal mean half-life of 61.8 +/- 15.9 h on day 17. STAT3 phosphorylation in PBMCs assessed in 6 pts receiving 4mg/d was reduced from 67.4 +/- 17.4% at baseline to 53.0 +/- 18.1% (p=0.001) after administration on day 1. Interestingly, reduction in tumor metabolism by PET CT on day 15 was observed in 4/8 pts receiving 4mg/d. A pt with heavily pretreated adenocarcinoma of lung at 5mg/d dose had partial response; another pt with metastatic endometrial cancer at 4mg/d dose experienced stable disease for 6 cycles. Conclusions: OPB51602 has an MTD of 5mg/d on this schedule, demonstrates inhibition of STAT3 phosphorylation, and evidence of clinical activity. Further proof of concept studies of OPB51602 are warranted.

Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human

PF-592379 is a potent, selective agonist of the dopamine 3 receptor, for the treatment of male erectile dysfunction and female sexual dysfunction.In vivo, PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route.Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic.Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing.

Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure

To investigate the effects of age and chronic heart failure (CHF) on the oral disposition kinetics of fluvoxamine. A single fluvoxamine dose (50 mg) was administered orally to 10 healthy young adults, 10 healthy elderly subjects and 10 elderly patients with CHF. Fluvoxamine concentration in plasma was measured for up to 96 h. With the exception of apparent distribution volume, ageing modified all main pharmacokinetic parameters of fluvoxamine. Thus, peak concentration was about doubled {31 +/- 19 vs. 15 +/- 9 ng ml(-1); difference [95% confidence interval (CI)] 16 (3, 29), P < 0.05}, and area under the concentration-time curve was almost three times higher [885 +/- 560 vs. 304 +/- 84 ng h ml(-1); difference (95% CI) 581 (205, 957), P < 0.05]; half-life was prolonged by 63% [21.1 +/- 6.2 vs. 12.9 +/- 6.4 h; difference (95% CI) 8.2 (2.3, 14.1), P < 0.01], and oral clearance was halved (1.12 +/- 0.77 vs. 2.25 +/- 0.66 l h(-1) kg(-1); difference (95% CI) -1.13 (-1.80, -0.46), P < 0.001]. A significant inverse correlation was consistently observed between age and oral clearance (r=-0.67; P < 0.001). The coexistence of CHF had no significant effect on any pharmacokinetic parameters in elderly subjects. Ageing results in considerable impairment of fluvoxamine disposition, whereas CHF causes no significant modifications. Therefore, adjustment of initial dose and subsequent dose titrations may be required in elderly subjects, whereas no further dose reduction is necessary in elderly patients with CHF.

Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmatics

Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC(4) synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC(4) synthase gene polymorphisms, were also investigated. The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV(1) after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC(4) synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug.

Pharmacokinetics of carisbamate (RWJ‐333369) in healthy Japanese and Western subjects

To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations. An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5-8; subsequently, 500 mg on days 9-12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry. Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80-125% limits, which are considered not to be of clinical significance. With dose-body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80-125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1-41.4 ml/h/kg and 11.5-12.8 h. Carisbamate plasma exposure (AUC) and C(max) in Japanese subjects is approximately 20-25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.

Pharmacokinetics and Ex Vivo Pharmacodynamic Antimalarial Activity of Dihydroartemisinin-Piperaquine in Patients with Uncomplicated Falciparum Malaria in Vietnam

Compared to healthy subjects, malaria patients show a reduction in the mean oral clearance (1.19 versus 5.87 liters/h/kg of body weight) and apparent volume of distribution (1.47 versus 8.02 liters/kg) of dihydroartemisinin in Vietnamese patients following treatment with dihydroartemisinin-piperaquine (Artekin) for uncomplicated Plasmodium falciparum. Dihydroartemisinin is responsible for most of the ex vivo antimalarial activity of dihydroartemisinin-piperaquine.

A bioequivalence study comparing two formulations of lopinavir/ritonavir capsules

This investigation was carried out to evaluate the bioavailability of a new single fixed-dose combination formulation of lopinavir and ritonavir, relative to reference product, Kaletra (133.3 mg lopinavir/33.3 mg ritonavir) capsules, manufactured by Abbott Laboratories, Chicago, IL, USA. The bioavailability study was carried out on 72 healthy male and female volunteers who received a single dose of 3 capsules (133.3 mg lopinavir/33.3 mg ritonavir) of the test (T) and the reference (R) products in the fasting state, in a randomized, balanced, 2-way crossover design. After dosing, serial blood samples were collected for a period of 72 hours. Plasma harvested from blood was analyzed for lopinavir and ritonavir by a sensitive and validated simultaneous liquid-chromatographic and mass-spectrometric (LC-MS/MS) assay. Mean oral clearance (Cl/F) values of the FDC were 4.92 and 23.54 l/h for lopinavir and ritonavir, respectively, the maximum plasma concentrations (C(max)), area under the plasma concentration-time curve up to the last measurable concentration (AUC(0-t)), and to infinity (AUC(0-infinity)), were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (t(max)) was analyzed assuming an additive model. The parametric confidence intervals (90%) were calculated by Schuirmann's two 1-sided t-test criteria. It was found that the test/reference (T/R) ratios for the pharmacokinetic parameters AUC(0-t), AUC(0-infinity) and C(max) (after initial log transformation) were well within the bioequivalence acceptance range of 80-125% as per international regulatory guidelines. Therefore, the two formulations were considered to be bioequivalent [Food and Drug Administration 2003].

Population Pharmacokinetic Analysis of Two Theophylline Formulations in Premature Neonates and Infants with Apnea

A study was conducted to clarify differences in the theophylline pharmacokinetics of two orally available products, theophylline alcohol and Apnecut, in premature neonates and infants using population pharmacokinetic analysis. Fifty-two patients with apnea hospitalized at the National Center for Child Health and Development were enrolled (total number of plasma concentration points=90). Population pharmacokinetic analysis under steady-state conditions was performed using NONMEM ver. V. The mean oral clearance was 0.0249 (l/h), and the inter- and intraindividual variation was 30.3% and 28.3%, respectively, in the basic model. The oral clearance was significantly affected by body weight, sex, and age. The final model obtained was expressed by the following equation: oral clearance (l/h)=0.0201 x (body weight (g)/1000)(1.08)x (1-0.282 x drug product), where theophylline alcohol is 0 and Apnecut is 1. The inter- and intraindividual variations in the final model were 15.0% and 15.3%, respectively. The oral clearance of the two oral formulations differed significantly, and this difference should be considered when adjusting the theophylline dose.