Effects of tesmilifene,a substrate of CYP3A and an inhibitor of P‐glycoprotein,on the pharmacokinetics of intravenous and oral docetaxel in rats

Objectives It has been reported that docetaxel is a P‐glycoprotein substrate and is metabolized via the cytochrome P450 (CYP) 3A subfamily in rats. Tesmilifene is a substrate of the CYP3A subfamily and is an inhibitor of P‐glycoprotein. Thus, the effects of various doses of tesmilifene on the pharmacokinetics of intravenous and orally administered docetaxel have been investigated in rats. Methods Docetaxel (20 mg/kg as base) was administered intravenously and orally without and with tesmilifene (5, 10, and 20 mg/kg) in rats. Key findings After intravenous administration of docetaxel with tesmilifene, the values of nonrenal clearance (CL_NR) and area under the plasma concentration–time (AUC) for docetaxel were comparable with those without tesmilifene. Tesmilifene did not increase the values of AUC or of absolute oral bioavailability (F) for docetaxel after oral administration of docetaxel with tesmilifene. Conclusions The inhibition for the metabolism of docetaxel via hepatic and intestinal CYP3A subfamily, and inhibition of P‐glycoprotein‐mediated efflux of docetaxel in the intestine by tesmilifene were almost negligible. The extremely low value of F for docetaxel was due to the incomplete absorption from the gastrointestinal tract and considerable first‐pass metabolism of docetaxel in rats.     

Population pharmacokinetics of valproate in Mexican children with epilepsy

Background. The aim of this study was to determine the factors that influence valproate clearance (CL) in Mexican epileptic pediatric patients using a mixed‐effect model and sparse data of serum concentrations of valproic acid (VPA) collected during routine clinical care of patients. Methods. The number of patients included in the study was 110. The population CL was calculated by using the NONMEM program. The following covariates were tested by their influence on CL: total body weight (TBW), height, age, body surface area, daily dose (DD), sex of the patient and comedication with phenobarbital (PB) or carbamazepine. Results. The final regression model for valproic CL found best to describe the data was: CL/F=(0.0466+0.00363 TBW+0.000282 DD) ^* (1+0.236 PB). This model allows a reduction of 50% of the interindividual variability and of 31% of the residual variability described by the basic model that does not include covariables. Conclusions. Total body weight, daily dose of valproate and concomitant therapy with PB are factors that significantly influence VPA kinetic disposition and they should be considered in programming dosage regimens for this antiepileptic drug in the pediatric population. The validation of the model supports its acceptability for clinical purposes. Copyright © 2008 John Wiley & Sons, Ltd.     

Impact of Concentrative Nucleoside Transporter 1 Gene Polymorphism on Oral Bioavailability of Mizoribine in Stable Kidney Transplant Recipients

Abstract: Mizoribine, an immunosuppressive anti‐metabolite, is largely excreted into urine in its unchanged form, and its pharmacokinetics has been considered to be dependent on the glomerular filtration rate. However, the pharmacokinetic disposition of mizoribine has not been fully clarified. The aim of this study was to evaluate the pharmacokinetic disposition of mizoribine based on polymorphism of concentrative nucleoside transporter (CNT) 1 gene in kidney transplant recipients. Thirty‐four Japanese stable recipients receiving an immunosuppressive regimen containing mizoribine for more than four months after transplantation were enrolled. Each recipient had been receiving a fixed dose of mizoribine for at least one month before enrolment. Oral bioavailability of mizoribine was obtained by dividing its amount in 24‐hr urine by the daily dose. The median and interquartile range of the dose‐normalized plasma concentration of mizoribine at 12 hr (C₁₂) were 6.11 and 3.47–10.9 ng/ml per mg, respectively. The median bioavailability of mizoribine was 44.8%, and interindividual variability was also observed (interquartile range, 37.8–61.5%). The correlation coefficient between creatinine clearance and substitute renal clearance (CL_MZ) estimated from the mizoribine C₁₂ was 0.65. The CNT1 G565A allele frequency was 51.5%. The mizoribine bioavailability was significantly lower in 565GA and AA than that in GG (median, 42.0%, 41.4% and 62.4%, respectively). No significant differences were observed in the dose‐normalized C₁₂ of mizoribine and substitute CL_MZ between the G565A genotypes. The mizoribine bioavailability was affected by CNT1 G565A in kidney transplant recipients. CNT1 G565A would contribute to interindividual differences in plasma disposition of mizoribine.     

Relative Importance of Intestinal and Hepatic Glucuronidation—Impact on the Prediction of Drug Clearance

Purpose  To assess the extent of intestinal and hepatic glucuronidation in vitro and resulting implications on glucuronidation clearance prediction. Methods  Alamethicin activated human intestinal (HIM) and hepatic (HLM) microsomes were used to obtain intrinsic glucuronidation clearance (CL_int,UGT) for nine drugs using substrate depletion. The in vitro extent of glucuronidation (fm_UGT) was determined using P450 and UGT cofactors. Utility of hepatic CL_int for the prediction of in vivo clearance was assessed. Results  fm_UGT (8–100%) was comparable between HLM and HIM with the exception of troglitazone, where a nine-fold difference was observed (8% and 74%, respectively). Scaled intestinal CL_int,UGT (per g tissue) was six- and nine-fold higher than hepatic for raloxifene and troglitazone, respectively, and comparable to hepatic for naloxone. The remaining drugs had a higher hepatic than intestinal CL_int,UGT (average five-fold). For all drugs with P450 clearance, hepatic CL_int,CYP was higher than intestinal (average 15-fold). Hepatic CL_int,UGT predicted on average 22% of observed in vivo CL_int; with the exception of raloxifene and troglitazone, where the prediction was only 3%. Conclusion  Intestinal glucuronidation should be incorporated into clearance prediction, especially for compounds metabolised by intestine specific UGTs. Alamethicin activated microsomes are useful for the assessment of intestinal glucuronidation and fm_UGT in vitro.     

Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model

1. Prediction of metabolic clearance in extreme individuals rather than the ‘average human’ is becoming an attractive tool within the pharmaceutical industry.

2. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CL_int) data from in vitro metabolic data and back-calculation from in vivo clearance data. Second, the sensitivity of predicted in vivo variability to changes in variability for physiological parameters (e.g. liver weight, haematocrit, CYP3A abundance). Finally, reported estimates of variability in hepatic CYP3A4 abundance (coefficient of variation (CV) 95%) were refined by separating experimental from interindividual variability using a repeat measurement protocol in 52 human liver samples.

3. Using in vitro metabolic data, predicted clearances were within 2-fold of observed for triazolam and midazolam. Clearance of alprazolam was overpredicted by 2.0- to 3.7-fold. Use of in vivo CL_int values improved prediction of intravenous clearance to within 2-fold of observed for all drugs.

4. Initially, the variability in clearance was overestimated for all drugs (by 1.8- to 3.6-fold). Use of a reduced hepatic CYP3A4 CV of 41%, representative of interindividual variability alone improved predictions of variability in clearance for all drugs to within 2-fold of observed.

     

Method for predicting human intestinal first-pass metabolism of UGT substrate compounds

1. As intestinal glucuronidation has been suggested to generate the low oral bioavailability (F) of drugs, estimating its effects would be valuable for selecting drug candidates. Here, we investigated the absorption and intestinal availability (F_aF_g) in animals, and intrinsic clearance via UDP-glucuronosyltransferase (UGT) in intestinal microsomes (CL_int,UGT) for three drug candidates possessing a carboxylic acid group, in an attempt to estimate the impact of intestinal glucuronidation on F and select potential drug candidates with high F in humans.

2. The F_aF_g values of the three test compounds were low in rats and monkeys (0.16–0.51), and high in dogs (≥0.81). Correspondingly, the CL_int,UGT values were high in rats and monkeys (101–731 µL/min/mg), and low in dogs (≤?59.6 µL/min/mg). A good inverse correlation was observed between F_aF_g and CL_int,UGT, suggesting that intestinal glucuronidation was a major factor influencing F_aF_g of these compounds.

3. By applying this correlation to F_aF_g in humans using human CL_int,UGT values (26.9–114 µL/min/mg), compounds 1–3 were predicted to have relatively high F_aF_g.

4. Our approach is expected to be useful for estimating the impact of intestinal glucuronidation on F in animals and semiquantitatively predicting human F for drug candidates.

     

Population‐based meta‐analysis of furosemide pharmacokinetics

Furosemide is a loop diuretic frequently used to treat fluid overload conditions such as hepatic cirrhosis and congestive heart failure (CHF). A population‐based meta‐analysis approach in NONMEM® was used to develop a PK model characterizing the time‐course of furosemide in plasma and excretion into the urine for healthy subjects and fluid overload patients. Furosemide PK data from healthy subjects receiving 80 mg of oral furosemide were supplemented with additional individual and aggregate plasma concentration and urinary excretion versus time data from the literature after intravenous (i.v.) or oral furosemide administration (10–500 mg) to healthy subjects or fluid overload patients. A three‐compartment model with zero‐order input following i.v. administration (or first‐order absorption using a Weibull function after oral administration) and first‐order elimination best described furosemide PK. A covariate analysis identified creatinine clearance (CL_CR) as a statistically significant predictor of renal clearance (CL_R), with a population mean CL_R of 4.67, 3.11, 1.95 and 1.17 l/h for a subject with normal renal function (CL_CR = 120 ml/min) or mild (CL_CR = 80 ml/min), moderate (CL_CR = 50 ml/min) or severe (CL_CR = 30 ml/min) renal impairment. Oral bioavailability was 59.1% and non‐renal clearance was 2.02 l/h. A PC‐VPC and other model diagnostics demonstrated that the population PK model can reasonably predict the rate of urinary furosemide excretion over time using dosing history and commonly available demographic data, allowing for convenient assessment of PK‐PD relationships for furosemide when given alone or in combination with other agents used to treat fluid overload conditions. Copyright © 2013 John Wiley & Sons, Ltd.     

Does alpha1-acid glycoprotein reduce the unbound metabolic clearance of disopyramide in patients with renal impairment?

Summary The pharmacokinetics of disopyramide was studied in 15 patients with renal dysfunction (4 with pyelonephritis, 7 with glomerular nephritis and 4 with interstitial nephritis).The elimination rate constant of unbound disopyramide was 0.094 h^–1 and CL_u/f (unbound clearance divided by bioavailability) was 245 ml/min. Both the unbound renal clearance (CL_R) and CL_u/f were highly correlated with the creatinine clearance (CL_CR). The apparent unbound metabolic clearance in the patients was approximately two-fold lower than that previously reported in normal subjects. The estimated unbound metabolic clearance in the renal dysfunction patients showed a significant negative correlation with the ₁-acid glycoprotein (AAG) concentration and only a weak, non-significant correlation with CL_CR.As AAG in the renal dysfunction subjects was increased in comparison with normal values, it is possible that AAG is a factor in the decrease in the apparent unbound metabolic clearance.     

Population pharmacokinetics of rosuvastatin: implications of renal impairment,race, and dyslipidaemia

ABSTRACT

Objectives: To build the structural model of pharmacokinetics for rosuvastatin and evaluate the impact of demographic characteristics including renal function on its pharmacokinetic parameters.

Methods: A population pharmacokinetic analysis of rosuvastatin in healthy volunteers, subjects with dyslipidaemia, and renal failure patients was performed using non-linear mixed-effects modelling and a two-compartment pharmacokinetic model with simultaneous first- and zero-order absorption. Demographic covariates, dyslipidaemic state and renal function were evaluated for their impact on pharmacokinetic parameters by step-wise additions or deletions using the likelihood ratio test.

Results: Typical pharmacokinetic parameters were estimated for a healthy white male subject. For example, apparent oral clearance (CL/F?) was estimated to be 257?L/h. Age, smoking status, weight, body surface area, and lean body mass had no significant effect on rosuvastatin pharmacokinetics. The model predicted that CL/F for subjects with creatinine clearance (CLCR?) of 30?mL/min (moderate renal impairment) and of 50?mL/min (mild renal impairment) was 17% and 9.7% lower, respectively, relative to subjects with CLCR of 94?mL/min, the data set median value. CL/F was reduced by 71.1% and 43.7% in subjects with dyslipidaemia and in Asian subjects, respectively.

Conclusions: Reduction of CL/F of rosuvastatin is not considered clinically significant for patients with mild-to-moderate renal impairment. Rosuvastatin CL/F was reduced in subjects with dyslipidaemia, but it is important to realise that the safety/efficacy profile of rosuvastatin has been well established in this population. However, the potential for increased exposure in Asian subjects should be considered when initiating rosuvastatin treatment or increasing dose in this population.     

Variability in the renal clearance of cephalexin in experimental renal failure

This study forms a part of an investigation into the extent to which the type of renal damage influences the renal clearance of drugs. We have already demonstrated an effect of different types of experimental renal failure (ERF) on the renal clearance of two cations: cimetidine, a drug that is filtered and secreted by the nephron, and lithium, which is filtered and reabsorbed by more than one segment of the nephron. In this report the renal clearance of cephalexin (CL _CEX )is investigated, a drug that has a different mode of renal elimination, since it is filtered, secreted, and reabsorbed by the proximal tubules. The aim was to extend our earlier studies to an organic onion, and to provide an opportunity to evaluate the feasibility of using the renal clearance of N-1-methylnicotinamide (NMN) to predict the renal clearance of anionic drugs in renal failure. Different models of sitespecific ERF have been developed in the rat; proximal tubular necrosis (induced by cisplatin), papillary necrosis (induced by 2-bromoethylamine), andglomerulonephritis (induced by sodium aurothiomalate or by antiglomerular basement membrane antibodies). Glomerular function (GFR)was assessed by the clearance of inulin (CL _NULIN ),and tubular function was assessed by the clearance of endogenous NMN (CL _NLM .Our results show that even if the models of ERF used were not absolutely site-specific, glomerular function and tubular function did not decrease to the same extent in the different ERF. Therefore, glomerulo-tubular imbalance existed, which is incompatible with the intact nephron hypothesis, i.e., the site of the damage along the nephron and not only the degree of renal dysfunction, is a potential source of variability in the clearance of certain drugs. The renal clearance ofcephalexin was estimated more accurately by CL_NMN than GFR (r= 0.90). We conclude that the clearance of the endogenous cation NMN can be used to predict the renal clearance of drugs that are not only filtered by the glomeruli but also secreted and/or reabsorbed by the proximal tubules, and in the limited examples investigated appears to apply to both anionic and cationic compounds. In this respect the GFRalone was not an adequate parameter for the prediction of the renal clearance of such drugs.     

Identification of polymorphisms in the 3′-untranslated region of the human pregnane X receptor (PXR) gene associated with variability in cytochrome P450 3A (CYP3A) metabolism

1. Single nucleotide polymorphisms in the 3′-untranslated region (3′UTR) of the human pregnane X receptor (PXR) gene might contribute to interindividual variability in cytochrome P450 3A (CYP3A) activity.

2. Genotype–phenotype associations involving PXR-3′UTR single nucleotide polymorphisms were investigated through in vitro (53 human livers from primarily White donors) and in vivo (26 mainly White or African-American volunteers) studies using midazolam 1′-hydroxylation and midazolam apparent oral clearance (CL/F), respectively, as CYP3A-specific probes.

3. PXR-3′UTR resequencing identified twelve single nucleotide polymorphisms, including two that were novel. Although none of the single nucleotide polymorphisms evaluated were associated with altered midazolam 1′-hydroxylation in the liver bank, both rs3732359 homozygotes and rs3732360 carriers showed 80% higher (p?<?0.05) CL/F compared with homozygous reference individuals. These differences in CL/F were even larger (100% and 120% higher, respectively; p?<?0.01) when only African-American subjects (n = 14) were considered.

4. Five major haplotypes were identified containing the PXR-3′UTR single nucleotide polymorphisms and previously identified intron single nucleotide polymorphisms. Although CL/F differences were not statistically significant within the entire study cohort, African-American carriers of Haplotype-1 (which includes both rs3732359 and rs3732360 variants) exhibited 70% higher median CL/F compared with African-American non-carriers (p?=?0.036).

5. The results identify rs3732359 and rs3732360 as PXR-3′UTR single nucleotide polymorphisms associated with higher CYP3A activity in vivo in African-Americans.

     

Estimation of renal secretory function for organic cations by endogenous N1-methylnicotinamide in rats with experimental renal failure

To assess whether the secretory clearance of N ¹-methylnicotinamide (NMN), an endogenous organic cation, represents renal tubular secretion of the organic cation, the relationship between the secretory clearance of NMN, CL _scn(NMN),and that of tetraethylammonium bromide (TEA), CL _scn(TEA),was examined in normal and experimental renal failure (ERF) rats. TEA was selected as a representative organic cation secreted by the kidney. ERF was induced by glycerol, folate, salicylate, uranium, and gentamicin, substances which have been demonstrated to produce specific damage to the kidney by pathophysiological studies. Glomerular filtration rate (GFR), CL _scn(NMN),and CL _scn(TEA) decreased significantly in most of ERF rats, while blood urea nitrogen (BUN) increased significantly in all ERF rats. There was a statistically significant correlation (r=0.952, p<0.001) between the endogenous CL _scn(NMN) and CL _scn(TEA) in both the normal and ERF rats. Correlation analysis revealed that CL _scn(NMN) was superior to GFR in the degree of relationship to CL _scn(TEA),but BUN could not be used as an index for the secretion of NMN or TEA. Although the plasma concentration of NMN in most of the ERF rats was much higher than that in the normal rats, it affected neither the urinary clearance of NMN itself nor the excretion of TEA. From these findings, we propose that CL _scn(NMN) can be used as an index to assess renal tubular function for the secretion of organic cations that are excreted by both filtration and secretion without reabsorption.Abstracted in part from a dissertation submitted by Chang K. Shim to the Graduate School, Division of Pharmaceutical Sciences, University of Tokyo, in partial fulfilment of the Doctor of Philosophy degree requirements. This study was supported by a grant-in-aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.     

The relation between type of renal disease and renal drug clearance in children

Summary It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction.Patients in group 1 (n=5) had intrinsic renal disease and those in group 2 (n=5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC.There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CL_R:CL_CR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CL_R:CL_CR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CL_CR=24 ml·min^–1·1.73 m^–2). In contrast, patients in group 2 (CL_CR=49) ml·min^–1·1.73 m^–2) had an average CL_R:CL_CR ratio less than 1 for both cefotaxime and desacetylcefotaxime, suggesting that renal tubular transport mechanisms did not remain functional in these patients.Our findings suggest that the effect of renal insufficiency on the renal elimination of cefotaxime and its metabolite desacetylcefotaxime may depend on the cause of renal insufficiency.     

Effect of uranyl nitrate-induced acute renal failure on the pharmacokinetics of sulfobromophthalein in rats

The effect of acute renal failure (ARF) on the pharmacokinetics of sulfobromophthalein (BSP) was investigated in order to elucidate if renal failure modifies the hepatic metabolism of drugs. ARF was induced by intravenous (iv) injection of uranyl nitrate (UN) to rats (5 mg/kg) five days before the experiment. Area under the plasma concentration-time curve (AUC) of BSP after portal vein (pv) injection increased by 2-fold and total body clearance (CL _t) decreased one half (p<0.01) in UN-induced ARF (UN-ARF) rats compared to the control rats. But the plasma disappearance of BSP afteriv injection did not differ significantly between control and UN-ARF rats. Since BSP is excretedvia the liver,CL _t representd the approximate hepatic clearance of BSP. Therefore, the decrease inCL _t represents a decrease in hepatic intrinsic clearance (CL _int) for BSP since plasma free fraction (f _p) of BSP was not affected by UN-ARF. The content of hepatic cytoplasmic Y-protein, which catalyzes BSP-glutathione conjugation and limits the transfer of BSP from blood to bile, increased significantly (p<0.01), however its binding activity (BA) for BSP was decreased significantly (p<0.01) by UN-ARF. The decrease inCL _int might have some correlation with the changed characteristics of hepatic Y-protein, specifically its decreased BA for BSP.     

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine,alone and in combination with diabetes mellitus induced by streptozotocin

Rats with liver cirrhosis induced by N‐dimethylnitrosamine (LC) and rats with LC with diabetes mellitus induced by streptozotocin (LCD) have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. Changes in the pharmacokinetics of drugs (mainly non‐renal clearance, CL_NR) in LC and LCD rats reported in the literature compared with respective control rats were reviewed. This review mainly explains the changes in the CL_NRs of drugs (which are mainly metabolized via hepatic microsomal cytochrome P450s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CL_int; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (f_p) and hepatic blood flow rate (Q_H) depending on the hepatic excretion ratio of the drug. Generally, changes in the CL_NRs of drugs in LC and LCD rats could be well explained by the above‐mentioned three factors. The mechanism of urinary excretion of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of the drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans. Copyright © 2014 John Wiley & Sons, Ltd.     

Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy

AIM

Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters.

METHODS

This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n = 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM.

RESULTS

A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL_cr). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy.

CONCLUSION

The developed model identified CL_cr and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.     

Non-linear mixed effect modeling of the time-variant disposition of erythropoietin in anemic cancer patients

Chemotherapy‐induced anemia is a frequent complication in cancer treatment. The aim was to develop a pharmacokinetic (PK) model that describes the time‐dependent decline of epoetin alfa (rHuEPO) clearance following thrice (t.i.w.) or once (q.w.) weekly subcutaneous injections in cancer patients using a population PK approach. Serum concentrations of rHuEPO were available retrospectively from a phase I study. A one‐compartment model with first‐order elimination described rHuEPO PK. Sequential zero‐ and first‐order (k_a) processes with duration (t_lag) characterized the absorption. Population PK analysis was performed using NONMEM. The influence of several covariates was tested. Model evaluation was performed using visual predictive check. Precision of parameter estimates was assessed by standard errors and confidence intervals determined by bootstrap analysis. Apparent clearance (CL/F) and volume of distribution (V_c/F) were 25.6% lower and 29.2% higher for q.w. than t.i.w. groups. RHuEPO was absorbed for 10% during 24.6 h through the zero‐order process. Following which 90% of the dose was absorbed through the first‐order process with k_a of 0.033 h^?1. The most significant covariates were the time‐dependent decrease of CL/F with an increase in body weight, a decrease in reticulocyte count, a decrease in hemoglobin baseline, an increase in total number of chemotherapy cycles, and platinum‐containing chemotherapy. AGE served as an important covariate on FRAC and k_a. Visual predictive check showed no deviation from observed values. The PK model adequately predicted rHuEPO concentration‐profiles in all individuals. Relevant covariates were identified and incorporated into the model. Copyright © 2010 John Wiley & Sons, Ltd.     

Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation

Objectives The objectives were to study the absorption kinetics and pharmacodynamics of two oral formulations of flecainide in patients with atrial fibrillation (AF) and to assess the relationship between pharmacokinetic parameters and the efficacy in restoring sinus rhythm. Methods The data of 54 patients included in a randomised, open, parallel-group study were used. Patients received an oral solution containing 300 mg flecainide and 20 mg cisapride or three tablets each containing 100 mg flecainide. The pharmacokinetic profile of flecainide was fitted using a one-compartment model with lag-time and first-order absorption. Results The tablets gave a maximum concentration (C _{max\ fit}) of 0.43±0.14 mg/l at 2.37±1.20 h. The oral solution resulted in a much faster peak concentration at 1.05±0.71 h (P<0.0001). The C _{max\ fit} of the oral solution of 0.60±0.17 mg/l was higher (P=0.0002) than that of the tablets, and interindividual variabilities of C _{max\ fit} were 28% and 33%, respectively. The absorption rate constant (ka) of the oral solution was twofold larger (P<0.0001). A higher ka (P=0.04) and a duration of AF less than 24 h (P=0.006) increased the probability of cardioversion. If atrial fibrillation lasted less than 24 h, only ka (P=0.016) was obtained as a significant variable in multivariate analysis. The linear models of QRS interval changes versus flecainide concentrations of both formulations had similar slopes with similar interindividual variabilities. Conclusions The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.     

Prediction of the pharmacokinetic parameters of reduced- dolasetron in man using in vitro-in vivo and interspecies allometric scaling

1. Dolasetron (Anzemet®) is apotent andselective 5-HT₃ receptor antagonist which is rapidly and extensively reduced to yield its major pharmacologically active metabolite, reduced dolasetron (RD). RD is further metabolized by CYP450 enzymes as well as undergoing renal excretion. As both in vitro and in vivo data on RD were available from animals andman, two approaches to predict the human pharmacokinetic parameters ofRD were assessed. 2. First, in vitro studies, using liver microsomes from animal species and man, were undertaken to measure V_max and K_m and to assess the intrinsic clearance (CL_int). With appropriate liver weight and liver bloodflow scaling factorsthe predicted in vivo metabolic clearance (CL_{m_pred}) was calculated. Human CL_{m_pred} was underestimated by a factor of 5 when it was calculated using the above scaling factors. As, in a prospective study, the observed human in vivo metabolic clearance (CL_{m_obs})is unknown, CL_{m_pred} was substituted into the least-squares correlation equation obtained from a plot of CL_{m_pred} against CL_{m_obs}, using animal data. The estimate of human CL_{m_obs} was improved as it was only underestimated by a factor of 1.5. 3. Second, allometric scaling of in vivo animal pharmacokinetic data, using body weight, was performed topredict pharmacokinetic parameters in man. Good predictions of human pharmacokinetic parameters of RD were obtained for plasma clearance (1.7 l/min predicted versus 1.6 l/min observed), half-life (6.0?h predicted versus 5.6?h observed), and volume of distribution (860.9 l predicted versus 770.4 l observed). 4. The integration of in vitro metabolic data from microsomes gave similar results to conventional allometric scaling, whereas the normalization of clearance by brain weight resulted in an approximately three-fold underestimation of human clearance. 5. For RD, a drug that is eliminated by both renal and metabolic clearance, retrospective conventional allometric scaling allowed accurate prediction of pharmacokinetic parameters in man, whereas in vitro-in vivo scaling resulted in an underestimation of in vivo CL_m. Although these results are somewhat at variance, ideally both scaling methods should be applied to improve the prediction of human pharmacokinetic parameters.