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PBPK modeling approach that was built from in vivo clearance values, to be able to predict pediatric PK, since it is the most accurate model for describing adult tramadol PK in healthy volunteers. In this approach, intrinsic clearance values are calculated from in vivo clearance values from healthy adult volunteers, using a well- stirred model, to obtain a PBPK model that accurately predicts the in vivo clearance. In addition, specific CYP4. PBPK model, which is described in the “MATERIALS AND METHODS” section. Pediatric predictions derived from this adult PBPK model are mechanistic because all relevant pathways observed in adults are used for predicting the PK in pediatrics, based on knowledge of functionality maturation in different tissues (e. Although in the adult PBPK model a CYP2. This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout. Pharmaceutical SAS Users Group China 2017 (July 6-8, 2017, Shanghai, China). A switch-over clinical trial was performed. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism and excretion (ADME. Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of. This study examines the administration of an antibacterial agent in the morbidly obese patient population. We specifically examined the use of cefepime, a fourth. Phoenix Winnonlin 6. Downloads Available)Sample Results From Member Downloads. To create more accurate search results for Phoenix Winnonlin 6. D6, a CYP2. B6- CYP3. A4, and a renal component were implemented, we only focused on prediction of the total, CYP2. D6 and renal clearance component for the pediatric populations, since in vivo reference data were available for these pathways. After having studied the adult in vitro metabolism in HLM, we assessed whether formation of the primary metabolites O- desmethyltramadol (ODT) and N- desmethyltramadol (NDT) in pediatric HLM is governed by the same enzymes as in adult HLM. The result of this experiment would indicate if our approach of applying known maturation functions (1. CYP4. 50 enzymes in adults to predict the pediatric clearance is valid. Therefore, in order to assess the fractional activity of ODT and NDT formation relative to adult HLM, pooled adult HLM were incubated with tramadol, as well as probe substrates DEX (CYP2. D6) and MDZ (CYP3. A4) in pediatric and adult HLM. Fractional activity is calculated by taking the ratio of the activity observed in pediatric HLM and the activity observed in pooled adult HLM, as described in the “MATERIALS AND METHODS” section. High fractional activities were found for ODT (1. Table II) which can be explained by the fact that we have observed a relatively low CYP2. D6 activity in the pooled adult HLM batch (data not shown). Because we also measured CYP2. D6 fractional activity for the probe substrate (Table II), we were able to calculate the difference between the measured CYP2. D6 (DEX) fractional activity and the theoretical (based on in vitro ontogeny) CYP2. D6 activity. This difference illustrates to what extent the measured CYP2. D6 activity deviates from what one would expect for a given age. Correction of the measured ODT fractional activity with the previously calculated difference, which yields “corr. ODT 1 M” and “corr. ODT 3 M” in Fig. 3b, confirms us that ODT formation in pediatrics, just as in adults, is CYP2. D6- mediated. Applying an analogous correction to NDT formation with measured MDZ activity yields predictions in Fig. CYP3. A4 activity at all. A possible explanation is that CYP3. A4 is not the only CYP enzyme contributing to the formation of NDT, also confirmed by other reports (1. This comparison at the in vitro level enabled us to validate the assumption that in adult as well as in early life, CYP2. D6 is the major isoform contributing to the metabolism of tramadol to O- desmethyltramadol, making this metabolite a valid probe to study CYP2. D6 maturation. Nevertheless, it would be valuable to test more pediatric batches in addition to the pediatric batches described in this study in order to compare/validate the ontogeny functions for the enzymes of interest over a broader age range. In addition, since the ontogeny data for different CYP4. This approach can serve as guidance for interpreting pediatric metabolism studies, e. A4 metabolite in combination with an anticipated low 3. A4 activity, e. g., may indicate CYP3. A7 involvement, if substrate overlap is expected. Pediatric PBPK predictions of tramadol were performed with the pediatric module of the Simcyp. At the in vivo level, the maturation of total tramadol clearance could be compared between PBPK- predicted and in vivo observed data sets (Fig. The clearance as a function of weight or PMA by the PBPK model is underpredicted compared to the in vivo maturation profiles. As has been described above, the clearance prediction for this PBPK model is based on three hepatic components (CYP2. D6, CYP3. A4, and CYP2. B6) and one renal component (GFR). Possible explanations for an underprediction are (i) incorrect maturation function for either of the implemented CYP enzymes, (ii) other metabolic pathways contributing to tramadol’s metabolism in pediatric life (FMO, CYP3. A7) (1. 2,3. 8), or (iii) neglecting other minor pathways in tramadol metabolism (1. Therefore, the total clearance of tramadol was decomposed in its constituents and compared to in vivo observations, when possible. To this end, (i) since we had strong in vitro proof that ODT is a good CYP2. D6 activity probe, we compared the predicted versus in vivo observed tramadol CYP2. D6 clearance increase, documented in Fig. Fig. Concerning the renal clearance maturation, we could only compare our PBPK predictions to the Win. Nonlin. The comparison of the renal clearance, plotted as a function of PMA, between PBPK and Win. Nonlin. As for the CYP2. D6 clearance maturation, PBPK predictions are in close agreement with the Hill maturation model (black) and the Win. Nonlin. So which in vivo model is the best representation of the CYP2. D6 clearance increase? Both the exponential and the Hill model are population PK models built on plasma observations for parent and ODT metabolite, and share an allometric relationship in their covariate structure, but the age models are respectively exponential and Hill- type. Furthermore, the exponential model is based on plasma observations for 5. L/7. 0 kg, whereas the Hill model incorporates plasma observations from 2. Because in neither model urinary data was included, we performed a Win. Nonlin. This allowed estimation of the ODT moiety- related volume and its associated clearance value, as well as volume and clearance of tramadol. Although the Win. Nonlin. We believe that the Hill model is the better representation of clearance maturation in pediatrics because this maturation function is physiologically more plausible, since the “developmental” processes of cells tend to reach their end state at a certain point in childhood, while “growth” processes take over the increasing elimination capacity of such organs. As the Hill model is also based on the larger data set, we choose the Hill model as a more correct in vivo model to compare the PBPK predictions against. It turns out that the CYP2. D6 clearance maturation from PBPK aligns much better with our Win. Nonlin. Finally, the maturation from birth to adult life is presented for total and CYP2. D6 tramadol clearance in Figs. The maturation increase for the total and the CYP2. D6 clearance seems to agree with the in vivo model in very early life, with CYP2. D6 absolute clearance values that are also in line with in vivo observed values. However, until the age of 1. PMA), both predicted clearance parameters display a relatively constant underprediction, which disappears again in adulthood. It might be that in children, the maturation of liver size as a function of bodyweight is underestimated, since demographic parameters in Simcyp. We acknowledge that choosing the ages where clearances deviate significantly from predictions can be subject to discussion, which again highlights the need for developing adequate evaluation techniques in PBPK. Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males. Abstract. Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 6. N=3. 4) and as an oral solution or immediate- release capsules once daily (qday) between 1. N=3. 2). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration–time curve) increased in a dose- proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 3. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 4. 00 mg qday dosing, serum uric acid reduction was 3. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated. Keywords: urinary excretion, urate lowering, URAT1, single and multiple doses, food effect, clearance. Introduction. Gout is the most common form of inflammatory arthritis. It affects approximately 9 million people in Europe, more than 8 million in the United States, and more than 3 million in Japan. Gout results from a metabolic disorder, hyperuricemia, where excessive concentrations of uric acid in the blood lead to deposition of monosodium urate crystals in and around the joints and other connective tissues. This causes chronic inflammation, leading to acute gout flares and potentially chronic arthritis with joint damage and disfiguring tophi, kidney stones, and chronic kidney disease. Hyperuricemia, typically defined in guidelines as serum uric acid (s. UA) > 6. 8 mg/d. L (> 4. 00 . In addition, there are uricuretic agents that enhance therapeutic increases in uric acid excretion from the kidney (ie, uricuresis). Lesinurad is a selective uric acid reabsorption inhibitor that inhibits the uric acid transporter 1 (URAT1) located in the proximal tubule of the kidney. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. By inhibiting URAT1, lesinurad acts as a uricuretic agent, promoting uricuresis and thereby lowering s. UA. 1. 0–1. 4The aim of the three current studies was to characterize the pharmacokinetic and pharmacodynamic profile and to evaluate the safety profile of lesinurad in healthy subjects when it is given in pharmacologically active doses. The single ascending dose (SAD) study was conducted using an oral solution of lesinurad, and the multiple ascending dose (MAD) study evaluated the oral solution and an immediate- release capsule. The relative bioavailability study compared the pharmacokinetics between capsules and tablets. Methods. The protocol and consent form were approved by the York- shire Independent Research Ethics Committee (Leeds, UK) prior to the start of the SAD and MAD studies, and approved by the Independent Investigational Review Board Inc. Only male subjects with body mass index within the range of . Eligible subjects were aged at least 1. SAD, MAD, and relative bioavailability studies, respectively. For all studies, eligible subjects had s. UA concentration . In the SAD study, each dose group included five subjects, of whom one received placebo and four a single dose of lesinurad oral solution from 5 mg to 6. The oral solution was prepared from amorphous lesinurad free acid. Subjects who were dosed in the fed state consumed a standard low- fat diet (1. Treatment with lesinurad was initiated with the lowest dose group, with an interval of at least a week between each dose level to allow the review of safety and pharmacokinetic data prior to progression to the next dose level. Each subject participated in one dose assessment only and remained in the clinical research unit (CRU) from day . The capsules contained lesinurad sodium salt. Groups were sequentially enrolled with an interval of at least 1. For subjects administered 1. Each subject participated in one study period only and remained in the CRU from day . It included eight subjects, and all subjects participated in each treatment period. Subjects consumed a low- fat breakfast (. No one received placebo. Subjects completed a 5- day washout period before administration of study drug in the next treatment period. Each subject remained in the CRU from day . During their confinement, subjects abstained from all food and beverages other than the scheduled meals provided by the CRU and water to quench thirst. Safety assessments for all three studies included adverse events (AEs) based on the medical review of AE reports and the results of vital sign measurements, 1. AEs were recorded throughout the study period and defined as any new medical occurrence or worsening of a preexisting condition after administration of the study drug or placebo. AEs were categorized according to the Medical Dictionary for Regulatory Activities and were reviewed for potential significance and clinical importance. Serious AEs were defined as AEs that resulted in death, hospitalization or prolongation of existing hospitalization; or persistent or significant disability or congenital anomaly; were life threatening; or were considered an important medical event. Sample collection. For all studies, venous blood samples were taken at predetermined times for determination of plasma concentrations of lesinurad as well as for determination of s. UA and serum creatinine concentrations. Urine samples were collected at predetermined intervals for determination of lesinurad, creatinine, and urate concentrations. Blood and urine samples were collected up to 7. SAD study, up to 4. MAD study, and up to 4. Sample analysis. Analysis of lesinurad plasma and urine concentrations for all studies was performed using high- performance liquid chromatography (HPLC) with tandem mass spectrometry. All determinations of lesinurad concentrations in human plasma and urine were generated in analytical runs using appropriate calibration curves and quality control samples that met preestablished acceptance criteria and were conducted in compliance with applicable standard operating procedures in place at the time of analysis. Plasma and urine samples were diluted for analysis. The standard curve ranges for lesinurad in plasma were 1 ng/m. L to 1,0. 00 ng/m. L in the SAD and MAD studies and 5 ng/m. L to 2,0. 00 ng/m. L in the relative bioavailability study. The standard curve range for lesinurad in urine was 1 ng/m. L to 1,0. 00 ng/m. L in all studies. The between- run and within- run coefficients of variation for the analytical quality controls in either matrix were . Creatinine was analyzed by established enzymatic methods. Pharmacokinetic analysis. Pharmacokinetic parameters for lesinurad were calculated using noncompartmental analysis. Plasma pharmacokinetic parameters included maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration–time curve (AUC) from zero to infinity (AUC. Cmax and Tmax were obtained from experimental observations. AUC was calculated using the linear trapezoidal rule. The apparent oral clearance (CL/F) was also determined. Urinary pharmacokinetic parameters included the amount of lesinurad excreted unchanged in urine over a time interval (Ae), the fraction of the lesinurad dose (% dose) excreted unchanged in urine following dosing (fe), and the renal clearance of lesinurad (CLR). Ae was calculated as concentration measured . Pharmacokinetic parameters were derived using Win. Nonlin Professional, version 5. Pharsight Corporation, St Louis, MO, USA). Pharmacodynamic analysis. Pharmacodynamic measurements included maximum observed percent changes from baseline (day . CLUR was calculated as Ae. UR divided by plasma urate AUC over the same time interval, while FEUA was calculated as (CLUR/Cr. Cl) . The pharmacodynamic parameters were determined using SAS version 8. SAS Institute Inc., Cary, NC, USA). Statistical analysis. Pharmacokinetics and pharmacodynamics were summarized using descriptive statistics. Data are presented as geometric mean and 9. CIs) for pharmacokinetic parameters. For pharmacodynamics, least squares means for each dose level and 9. CIs for the mean differences for each pairwise treatment difference were calculated. Placebo was pooled across all groups in the SAD and MAD studies. No adjustments for multiple comparisons were made. Pharmacokinetic–pharmacodynamic relationships were explored graphically. Dose proportionality assessment for Cmax and AUC was performed using a power model,1. Ln(AUC) or Ln(Cmax) = a + b*Ln(Dose)(1)When slope b is close to unity 1 with 9. CI around b within the 0. Results. Subjects. A total of 3. 4 subjects enrolled in and completed the SAD study, while 3. MAD study. There were eight subjects who enrolled in and completed the relative bioavailability study. The demographic and baseline characteristics of subjects in each study are shown in Table S1; the groups in each study had similar demographic and baseline characteristics. SAD study. The median plasma concentration–time profiles for healthy subjects administered lesinurad oral solution at single doses ranging from 5 mg to 6. Figure 1. A. Lesinurad was rapidly absorbed, with a median Tmax of 0. Table 1). Mean estimated terminal t. This outlier value is likely attributed to individual subjects with anomalously higher concentrations in the terminal phase that led to greater calculated terminal half- lives. Total oral clearance of lesinurad ranged from 9. L/min, indicating that lesinurad is a low clearance drug (compared with hepatic blood flow as high as 1. L/min). In urine, unchanged drug ranged from 1. |
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