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Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations., (© 2023, The American College of Clinical Pharmacology.)

Objective: To evaluate serum pharmacokinetics of tapentadol administered to healthy subjects as extended-release (ER) tablets., Design: Seven single-dose studies (five randomized, crossover, bioequivalence studies; a study in Japanese men; and a randomized, crossover, effects-of-food study) and one repeated-dose study., Setting: Clinical research settings in the United States and The Netherlands., Patients or Participants: Healthy males and females were enrolled into seven studies; one study enrolled only Japanese males., Interventions: In the bioequivalence studies, subjects first received one polyethylene oxide- or hypromellose-based tapentadol ER tablet (50, 100, 150, 200, or 250 mg; one dose per study), then (after washout) the other formulation (matching dose). In all other studies, subjects received polyethylene oxide-based tapentadol ER tablets. In the repeated-dose study, subjects received one 250 mg tablet, then (after washout) one 250 mg tablet every 12 hours (five doses). In the food-effect study, subjects received one 250 mg tablet within 30 minutes after a high-fat meal or after 10 hours of fasting. In the study in Japanese men, subjects received one 100 mg tablet., Main Outcome Measures: Maximum tapentadol concentrations (Cmax) were typically observed 5 hours after dosing. Mean terminal half-life values ranged from 4.4 to 5.9 hours. Tapentadol Cmax and AUC values increased proportionally following single ER (polyethylene oxide-based tablets) doses of 50 to 250 mg. Trough tapentadol concentrations increased during repeat dosing until reaching steady-state by the third dose. Serum Cmax and area under the concentration-time curve (AUC) values at steady state were 1.6 and 1.9 times higher relative to single-dose administration. Coadministration of the 250 mg dose with a high-fat meal increased Cmax and AUC values by an average of < 17 percent., Conclusions: The pharmacokinetics of tapentadol ER are consistent after repeated and single-dose administration. Tapentadol ER may be administered without regard to food intake. No clinically significant differences were observed in the pharmacokinetics of tapentadol between Japanese and Caucasian subjects.

RG 12525 (2-[[4-[[2-(1H-tetrazole-5-ylmethyl)phenyl]methoxy]phenoxy]methyl] quinolone) is a novel peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist. In vitro microsomal inhibition assays indicated that RG 12525 is a potent inhibitor of CYP3A4, with a Ki value of 0.5 microM. With the conservative assumption that the total plasma concentration of drug was available to metabolic enzymes following RG 12525 oral administration, marked inhibition of CYP3A4 was expected to substantially reduce the systemic clearance of compounds metabolized by this enzyme. The possibility also existed for inhibition of intestinal and hepatic CYP3A4 by RG 12525 to reduce "first-pass" metabolism and increase absolute bioavailability of CYP3A4 substrates orally coadministered. Consequently, an in vivo drug-drug interaction study was performed to evaluate the effects of orally administered RG 12525 on in vivo CYP3A4 activity in healthy male subjects. The pharmacokinetics of oral midazolam, a probe for intestinal and hepatic CYP3A activity, was not influenced by either the low (100 mg qd for 4 days) or high (600 mg qd for4 days) RG 12525 dosing regimen despite the resulting total plasma concentrations of inhibitor that were well above in vitro Ki values. The point estimates and 90% confidence intervals for the ratios of mean midazolam AUC for subjects administered 100 mg RG 12525 (110.6; 98.7-124.1) and 600 mg RG 12525 (98.4; 84.4-114.7) versus midazolam alone were within 80% to 125%. To explain these results, factors that could limit the accuracy of in vitro models in predicting metabolic drug interactions, mainly the high degree of RG 12525 protein binding (> 99.9%), were considered. The lack of correlation between the in vitro inhibition of CYP3A4 by RG 12525 and the inconsequential effects of this compound on midazolam pharmacokinetics accentuate the need to recognize factors other than plasma drug concentrations and potency of in vitro enzyme inhibition when extrapolating in vitro data to predict in vivo drug-drug interactions.

ARA is an adenosine receptor agonist with high affinity for A1 and A2 receptors, which are involved in regulation of free fatty acid (FFA) production. Two parallel groups of 13 healthy males were enrolled in a Phase I study to evaluate the pharmacokinetics of this compound and to characterize its effect on plasma FFA concentrations following administration of a single 6-hour intravenous infusion of ARA or placebo. ARA plasma concentrations were measured by a validated high-performance liquid chromatographic method (fluorescence detection). ARA is a highly cleared compound (Cl: 0.79 L/h/kg) with a modest volume of distribution (Vss: 0.91 L/kg) and short half-life (t1/2: approximately 1 hour). The mean percent change in plasma FFA concentrations relative to placebo was best described by an Emax-based tolerance model, in which a hypothetical metabolite/antagonist was used to describe the apparent development of tolerance to the suppressive effects of ARA on FFA levels. The EC50 values (%RSE of estimate) for ARA and the hypothetical antagonist were 17.0 (5.4) and 15.6 (12.8) ng/mL, respectively. The use of adenosine A1 agonists as antilipolytic drugs may be restricted due to the potential development of tolerance, and thus a period of abstinence from the agonist may be required before the response of FFA returns to pretolerant conditions. In the case of ARA, the value of 0.33 h-1 for Kant0 indicates that a period of approximately 11 hours should suffice. In agreement with preclinical data previously reported in literature, the present study provides evidence that desensitization of adenosine receptor-mediated inhibition of lipolysis may occur in humans. In conclusion, the ability of ARA to reduce circulating levels of FFA can be related to plasma ARA concentrations using a modified Emax-based tolerance model.

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD891 and RGD039 were measured by validated LC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectively. PD activity was assessed by percent inhibition of ADP (20 microM)-induced platelet aggregation. Following intravenous dosing, the RGD891 was the predominant compound in plasma. The PK of RGD891 was dose independent associated with modest between-subject variability. RGD891 was rapidly cleared (Cl, 11.2-15.5 L/h), exhibited a restricted distribution (Vss, 23.0-25.9 L) and a short terminal t1/2 lambda z (1.2-2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had longer t1/2 lambda z of 4.5 to 6.6 hours. Renal excretion of unchanged drug played an important role in the elimination of the parent compound. Both RGD891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effectively inhibited platelet aggregation in a dose-dependent and reversible manner. At the highest dose (60 micrograms/kg bolus dose + 336 micrograms/kg 8-h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primarily attributed to the parent compound. Inhibition of platelet aggregation was dependent on the anticoagulant present, with samples containing PPACK showing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studies.

Unlabelled: RGD891 is a platelet GPIIb/IIIa receptor antagonist and potent inhibitor of platelet aggregation. This compound is biotransformed in vivo to RGD039, which also exhibits high affinity for the GPIIb/IIIa receptor. Pharmacokinetic/pharmacodynamic modeling was employed to describe the concentration-effect relationship of both compounds following the intravenous administration of RGD891 to healthy volunteers. The overall objectives of this work were to support the dose selection process for future intravenous RGD891 safety and efficacy studies. Various intravenous regimens of RGD891 were administered to healthy volunteers enrolled in three Phase I studies. Frequent plasma samples were collected at regular intervals for later measurement of RGD891 and RGD039 concentrations (validated LC/MS/MS methods). The pharmacokinetics of RGD891 and RGD039 were simultaneously analyzed by nonlinear mixed-effect modeling (NONMEM). Pharmacodynamic activity was assessed in all three studies by the degree to which ADP (20 microM)-induced platelet aggregation was inhibited. Population parameters describing the concentration-effect relationship of RGD891 and RGD039 were then generated using a modified competitive Emax-based model., Results: Parent compound is by far the predominant active compound circulating in the plasma following intravenous administration of RGD891. The plasma RGD891 concentration-time data were best fit by a two-compartment structural model. The fit of the basic model was improved when total body weight was introduced as a covariate for RGD891 distribution. Between-subject variability in the RGD891 pharmacokinetic parameters--V1, K10, and K21--was less than 17% (coefficient of variation). Formation of the active metabolite (RGD039; Km) and its elimination (Kem) were assumed to be first-order processes (i.e., one-compartment model). The population pharmacokinetic model could only provide a rough estimate of the plasma concentration-time profile for RGD039 after administration of a given intravenous dosage regimen of RGD891 since metabolite concentrations were relatively low and highly variable. The first-order rate constant describing the formation of RGD039 from RGD891 (Km) was also associated with a substantial degree of between-subject variability (44.9%). The potency of RGD891 toward the inhibition of ADP-induced platelet aggregation was described by the population IC50 value (plasma concentration yielding 50% of maximal inhibition), which ranged from 58.0 to 95.4 ng/mL, depending on the pharmacokinetic-pharmacodynamic (PK-PD) model and the data set used. The relatively low concentrations of the active metabolite achieved following intravenous administration of RGD891 did not permit independent estimation of a population IC50 value for RGD039. Therefore, its potency was fixed at 2.2-fold greater than that of the parent compound (based on previous PK-PD analyses). Intersubject variability in the IC50 values was 30%., Conclusions: Antagonism of the platelet IIb/IIIa receptors by intravenously administered RGD891 was effective in inhibiting ADP-induced platelet aggregation in a reversible and dose-dependent manner. Pharmacodynamic activity was largely attributed to the parent compound and less to the active metabolite based on the relative potencies of both compounds and the plasma concentrations of each achieved following intravenous administration. Intravenous bolus plus maintenance infusion regimens resulted in rapid attainment of steady-state plasma RGD891 concentrations. This combination regimen also provided for a marked and sustained inhibition of platelet aggregation that reached 90% or greater (relative to baseline values) in the higher dose groups. The modified Emax model adequately described inhibition of platelet aggregation following a particular intravenous dosage regimen of RGD891 (within the range of doses administered in the present studies). (ABSTRACT TRUNCATED)

The pharmacokinetics of an adenosine agonist (AMP 579) were characterized in patients with end-stage renal disease compared to sex- and age-matched healthy volunteers. All study participants were administered single AMP 579 doses of 50 micrograms/kg as a 6-hour, constant-rate intravenous infusion. Serial blood samples were obtained for measurement of plasma AMP 579 concentration, and predose samples were collected for determination of AMP 579 plasma protein binding. The safety of AMP 579 administration in renally impaired patients also was evaluated. AMP 579 was rapidly cleared from the systemic circulation in all subjects as plasma concentrations were below the limit of detection by 2 to 4 hours after terminating the infusion. Noncompartmental analysis yielded mean values for the plasma AMP 579 concentration at the end of the 6-hour infusion (C6 h) of 9.6 and 10.5 ng/mL and for systemic clearances (Cl) of 0.91 and 0.72 L/h/kg in renally impaired patients and healthy volunteers, respectively. Mean volumes of distribution (Vss) in the renally impaired and healthy volunteers were 0.92 and 0.84 L/kg, and terminal elimination half-life values (t1/2) were 1.61 and 1.33 hours, respectively. The extent to which AMP 579 is bound to plasma protein was not altered in renally impaired patients since the free fractions were 4.0% and 3.4% for renally impaired and healthy volunteers, respectively. It was concluded that the pharmacokinetic parameters of AMP 579 were similar in both groups. The 6-hour AMP 579 infusion was generally well tolerated by both renal patients and healthy volunteers. There were no serious adverse events, and there were only two mild adverse events in 1 renally impaired patient judged possibly related to the study drug that quickly resolved. There were no clinically significant changes in laboratory values or clinical evaluations during the study. There was a slight increase in heart rate during the infusion of similar magnitude for both the renal patients and healthy volunteers. These data suggest that AMP 579 may be administered to renally impaired patients with minimal cardiovascular effects and adverse events. These results in end-stage renal patients (worst-case scenario) indicate that dose adjustment in patients with renal insufficiency of any degree is not indicated in future studies of AMP 579.

The pharmacokinetics of an adenosine agonist, AMP 579, following intravenous administration were evaluated. Single AMP 579 doses of 20 to 150 micrograms/kg were infused intravenously over 6 hours using a constant-rate or two-step rate of infusion to healthy male volunteers. Plasma and urine samples were collected for measurement of AMP 579 concentration using a validated HPLC assay. An assessment of safety and tolerability was also performed. Based on a noncompartmental method of analysis, the pharmacokinetics of AMP 579 were characterized by rapid systemic clearance (0.77 to 0.85 L/h/kg), a moderate steady-state volume of distribution (0.80 to 0.94 L/kg), and a short terminal elimination half-life (0.84 to 1.13 h). AMP 579 exhibited dose (infusion rate)-proportional pharmacokinetics over the dose range. In addition, little or no unchanged AMP 579 was found in the urine. The primary cardiovascular pharmacodynamic response that was observed was a dose-related increase in mean ventricular heart rate. Fifteen minutes prior to the end of the infusion, volunteers administered the highest dose (150 micrograms/kg) exhibited a mean (range) 59% (36%-69%) increase in heart rate as compared to a mean (range) 18% (0%-73%) increase for the placebo group. No clinically relevant changes in the systolic or diastolic blood pressure were observed. The information obtained in this study should allow the design of AMP 579 dosage regimens that would maximize plasma AMP 579 concentrations and minimize the incidence of adverse events.

A randomized, double-blinded, placebo-controlled pharmacokinetic and safety trial was conducted to determine the effect of fluconazole on methadone disposition. Volunteers receiving methadone maintenance therapy were randomized to receive either 200 mg/day oral fluconazole (n = 13) or placebo (n = 12). After 14 days there was a 35% average increase in serum methadone area under the curve relative to baseline among patients receiving fluconazole (p = 0.0008). At the same time, mean serum methadone peak and trough concentrations increased by 27% (p = 0.0076) and 48% (p = 0.0023), respectively, and oral clearance of methadone was reduced by 24% (p = 0.0007). In contrast, the pharmacokinetics of methadone were unaltered in the placebo group. Renal clearance of methadone was not significantly affected by fluconazole or placebo therapy. Although exposed to increased concentrations of methadone, patients treated with fluconazole did not exhibit signs or symptoms of significant narcotic overdose.

In this study, the overfed rat was employed as a model for examining the influence of obesity on the regulation of hepatic cytochromes P450 3A and 2C11 (CYP3A and CYP2C11, respectively). These proteins represent the predominant constitutive hepatic P450 enzymes of male rats. Sprague-Dawley rats were chronically fed a standard pelleted diet or an energy-dense diet which typically results in significant increases in body weight, serum triglyceride levels and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P450 content. Similar baseline activities of CYP3A (testosterone 6 beta-hydroxylation), comparative CYP3A protein levels (Western blot) and steady-state CYP3A mRNA (slot blot), were found in rats fed either diet. Likewise, obesity did not appear to influence CYP2C11 at the enzyme activity (testosterone 2 alpha-hydroxylation) or mRNA levels. Half of the animals in each group received 20 mg phenobarbital (intraperitoneal injection) per animal every 12 hours for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of total cytochrome P450 in both lean and obese rats to the same extent. CYP3A activity, protein and mRNA levels were induced to a similar magnitude in rats fed either diet. Furthermore, obesity did not influence CYP2C11 activity or mRNA levels following administration of phenobarbital. A lack of an effect of obesity and the altered lipid environment on the regulation of CYP3A and CYP2C11 is in contrast to other enzymes studied previously. It is apparent that the consequences of obesity on hepatic cytochrome P450 may be enzyme-specific.

The present study describes the effects of 2,2',4,4',5,5'-hexachlorobiphenyl, a "phenobarbital-like" inducer of hepatic cytochrome P450, on the CYP2B1 and CYP2B2 enzymes in the phenotypically obese fa/fa Zucker rat. The fa/fa Zucker rat demonstrated a markedly lower level of CYP2B1/2B2 enzyme induction, as indicated by reduced enzyme activity (testosterone 16 beta-hydroxylation and pentoxyresorufin O-dealkylation), protein concentration (Western blot), and mRNA (slot blot) than the lean Fa/? rodents after in vivo treatment with 2,2',4,4',5,5'-hexachlorobiphenyl. A primary hepatocyte cell culture system was used to control for possible differences in the disposition of 2,2',4,4',5,5'-hexachlorobiphenyl and hormonal dissimilarity between obese and lean Zucker rats. In agreement with the in vivo study, hepatocytes from fa/fa Zucker rats treated with 2,2',4,4',5,5'-hexachlorobiphenyl exhibited a poor induction response based on measurement of CYP2B1/2B2 mRNA. These data are similar to those reported earlier that demonstrate resistance of the CYP2B1/2B2 genes to the inductive effects of phenobarbital in fa/fa Zucker rats. Apparently a genetic defect in obese Zucker rats impairs the increase in CYP2B1/2B2 gene transcription after treatment with phenobarbital as well as 2,2',4,4',5,5'-hexachlorobiphenyl. This study provides evidence that phenobarbital and "phenobarbital-like" inducers share a common cellular element(s) in the induction process of the CYP2B1/2B2 enzymes.

Human obesity is associated with a number of pathophysiologic processes, such as fatty infiltration and fibrosis of the liver. Although obesity has been shown to alter the metabolism of various xenobiotics, its effect on hepatic cytochromes P-450 is not known. In this study, the overfed rat was used as a model for examining the influence of obesity on the expression and regulation of hepatic cytochrome P-450 2B1/2B2. Sprague-Dawley rats were fed either a standard diet or an energy-dense diet for 32 weeks. The energy-dense diet resulted in a significant increase in body weight, serum triglyceride levels, and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P-450 content. Similar baseline activities of CYP2B1/2B2 (16 beta-testosterone hydroxylase and pentoxyresorufin O-dealkylation)--comparative protein levels of CYP2B1/2B2 (Western blot), and mRNA (slot blot)--were found in rats fed either diet. Half of the animals in each group were given 20 mg phenobarbital (intraperitoneal injection)/animal every 12 hr for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of cytochrome P-450 in both groups to the same extent. However, greater CYP2B1/2B2 activity was found in control rats following phenobarbital administration, whereas the amount of protein and mRNA was similar in each treated group. In conclusion, obesity did not affect the regulation of CYP2B1/2B2 enzymes. However, changes in the lipid environment associated with obesity may have affected the activity of these proteins.

A near-infrared (IR) spectrophotometer, integrating optics, and parallel-vector supercomputer are employed to develop a mathematical model that predicts the dissolution rate of individual intact tablets from near-IR spectra (r2 = 0.985). Each tablet can be analyzed nondestructively by the spectrophotometer in less than 1 min. The model permits hundreds of near-IR wavelengths to be used in the determination of dissolution rate, leading to increased accuracy.