Pharmacokinetic Curves Research Articles

A strategy to calculate cyclosporin A area under the time-concentration curve in pediatric renal transplantation.

The complete area under the time-concentration curve (AUC) is considered the gold standard for cyclosporin A (CsA) monitoring, particularly in pediatric kidney graft recipients who have great absorption and drug clearance variability. However, complete AUC is time-consuming and expensive. For this reason, we retrospectively reviewed 131 complete 4-h AUC (AUC0-4) performed in 34 children (mean age 10.6 +/- 2 yr) in order to construct an equation to calculate AUC0-4. The median time after transplantation was 540 (range: 247-1,358) days. Multiple regression analysis was performed either with a single variable or with a combination of two variables. CsA blood concentration at the second hour after the oral morning dose (C2) was the best predictor of AUC0-4, where AUC0-4 = 424 + (2.65 x C2), R2 = 0.81, p < 0.001. Only the combination of C1 and C2 offered mathematical improvement over the C2 equation. The same analysis was made for pharmacokinetic curves performed earlier than 6 months (79 +/- 55 days, range 8-169 days) and after 1 yr of transplantation. In both time-periods, C2 was the best parameter to use to calculate AUC0-4. The equations obtained during these two time-periods were very close to the one for the whole population. Our data shows that C2 can be safely used to estimate AUC0-4. However, for values above 4,000 ng/h/mL, the formula overestimates the trapezoidal AUC0-4. The C2 equation simplifies the CsA monitoring as a result of its high predictive value and clinical feasibility.

Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is frequently used as part of the currently recommended combination therapy in the treatment of HIV-1 infection. NVP has been proven to be safe and effective, but when administered in suboptimal regimens, highly drug-resistant virus emerges rapidly limiting future options for treatment. Patient characteristics (e.g. demographics, co-morbidity) may have a large impact on the pharmacokinetics of nevirapine. Therefore, we explored the population pharmacokinetics of NVP in an unselected cohort of HIV-1-infected individuals. Included patients were ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, The Netherlands. Data were retrospectively collected from January 1997 to April 2000. The pharmacokinetics of NVP were described with a one-compartment model with first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (clearance (CL/F), volume of distribution (V/F), absorption rate constant (Ka)) were estimated. Interindividual (IIV) and interoccasion variability (IOV) were estimated with a proportional error model. Furthermore, the influence of patient characteristics on the pharmacokinetics of NVP were determined. From a small fraction of patients, baseline liver function test results were not available. In order to avoid bias, a covariate was included in the model indicating missing data. From 173 outpatients a total number of 757 NVP plasma concentrations at a single random timepoint and full pharmacokinetic curves of 13 patients were available resulting in a database of 1329 NVP plasma concentrations. CL/F of NVP was 3.49 l h−1 with an IIV and IOV of 28 and 21%, respectively. V/F was 93.1 l (IOV=46%) and the Ka was 1.65 h−1 (IIV=60%). CL/F of NVP was correlated with weight (WT), chronic hepatitis C infection (HepC), ASAT>1.5×upper limit of normal (ULN) at baseline, and the black race (RACE). These correlations are described by the following equation: CL/F=(3.49+0.0205×[WT-70])×0.483HepC× 0.66ASAT×(1−MISS)×0.671MISS×0.731RACE, in which HepC is 1 for individuals with hepatitis C infection and 0 for all others, ASAT is 1 for patients with baseline ASAT>1.5×ULN and 0 for all others, MISS is 1 for patients with no baseline ASAT value and 0 for all others, and RACE is 1 for black patients and 0 for all others. Thus, HepC, ASAT>1.5×ULN, and the black race reduce CL/F of NVP by 52%, 34%, and 27%, respectively, whereas an increase in WT of 10 kg increases the CL/F by 0.21 l h−1. The pharmacokinetics of NVP were adequately described with the developed population pharmacokinetic model. Weight, chronic hepatitis C infection, baseline ASAT>1.5×ULN, and the black race were found to be significant covariates for CL/F of NVP. The described model including these significant covariates could be an aid in optimizing NVP-containing therapy.

Interference of Sub-Inhibitory Concentrations of Gatifloxacin on Various Determinants of Bacterial Virulence

The physico-chemical characteristics of the molecular array on the outermost surface of bacteria modulate various bacterial functions which, when expressed in the human environment, constitute important determinants of bacterial virulence.The present study investigated the ability of subinhibitory concentrations of gatifloxacin to interfere with various virulence determinants of Escherichia coli and with the adhesiveness of Staphylococcus aureus. The adhesiveness of S. aureus and E. coli to human epithelial cells was inhibited at gatifloxacin concentrations down to 1/32 and 1/64 the minimum inhibitory concentration (MIC). Sub-MICs of gatifloxacin down to 1/8-MIC significantly reduced hemagglutination and hydrophobicity, which are correlated with fimbriation and provide clues relating to the physico-chemical characteristics of the outer surface of bacteria. Swarming (motility) was reduced at concentrations down to 1/8 MIC. Phagocytosis was not affected but killing significantly increased from 1/8 to 1/2 MIC.The respiratory bursts of neutrophils investigated by a chemiluminescence procedure were not modified. The interpolation of these pharmacodynamic findings with pharmacokinetic curves indicates that the effect of sub-MIC concentrations of gatifloxacin can engender activity, prolonging antimicrobial effects on virulence determinants over 30 hours after the antimicrobial concentration has fallen below the MIC.

Recent advances in therapeutic monitoring of cyclosporine: Absorption profiling

Cyclosporine (CsA) is an important component of many contemporary immunosuppressive regimens. Because of its narrow therapeutic window, therapeutic drug monitoring is essential. However, after almost 2 decades of clinical experience, the optimal monitoring method remains unclear. CsA trough concentration levels (C 0 ) have been widely used for monitoring despite poor correlation with clinical events and drug exposure measured by area under the concentration-time curve. The latter has better correlation with acute rejection and graft survival, but it is expensive, time consuming, and cumbersome. With the introduction of CsA microemulsion formula (CsA-ME), limited sampling methods to estimate drug exposure and measurement of single postdose CsA concentrations have been examined for their potential monitoring role in optimizing CsA use. Absorption profile, which expresses drug exposure during the most variable portion of the pharmacokinetic curve, has emerged as a more effective measure of therapeutic drug monitoring than trough concentrations. The 2-hour postdose concentration is the most practical surrogate for absorption-profile monitoring and will likely replace C 0 for monitoring CsA-ME preparations. We present a summary of pertinent studies in this field.

Reduction of animal usage by serial bleeding of mice for pharmacokinetic studies: application of robotic sample preparation and fast liquid chromatography–mass spectrometry

Typically, pharmacokinetic studies in mice require one animal per time point, thus resulting in differences due to dosing error, animal to animal variation and more importantly the euthanasia of a large number of animals. A method for the determination of pharmacokinetic data from serially bled mice to support early drug discovery is described. Sample analysis relies on liquid chromatography coupled with tandem mass spectrometry permitting robust and reproducible analysis requiring approximately 3 min per sample. Several parameters are discussed including the method of sample collection, preparation and analysis. The use of serially bled mice has lead to a remarkable reduction in animal usage and a corresponding reduction in compound required for such experiments. Using conventional methodology, a nine-point pharmacokinetic curve with four animals per time point would require 36 mice. With the method described below, only four mice in total are used and euthanasia is not required, permitting reuse after several weeks recovery and washout. Also, pharmacodynamic–pharmacokinetic correlation is possible and is demonstrated using a mouse model of diabetes.

Pharmacokinetics of ethanol in mice with different alcohol motivation.

We studied the pharmacokinetics of (14)C-ethanol administered in various doses and via different routes to CBA, C57Bl/6, and (CBAxC57Bl/6)F1 mice. Kinetic scheme of ethanol distribution included its elimination by enzymatic (80-90% C(0)) and exponential (10-20% C(0)) mechanisms. Ethanol pharmacokinetics did not depend on the administration route and mouse strain. The kinetic scheme of ethanol distribution in mice was characterized by a dose-dependent linear increase in alcohol concentration in the plasma and brain and nonlinear (parabolic) increase in the area under its pharmacokinetic curve in the test tissue.

Comparison of Capillary Electrophoresis with HPLC for Diagnosis of Factitious Hypoglycemia

The diagnosis of "factitious hypoglycemia" is essentially based on the disclosure of hypoglycemic agents in blood or urine. The aim of this study was to evaluate the performance of capillary electrophoresis (CE) as a quantitative method for determination of chlorpropamide, tolbutamide, glipizide, gliclazide, and glibenclamide in serum. Serum samples (1 mL), with internal standard added, were purified by solid-phase extraction on OASIS(TM) HLB cartridges (Waters), dried under reduced pressure, and reconstituted with 30-60 microL of acetonitrile:H(2)O. Analysis was carried out by micellar electrokinetic capillary chromatography in 5 mmol/L borate, 5 mmol/L phosphate, 75 mmol/L sodium cholate, pH 8.5, containing 25 mL/L methanol. Separation was accomplished in a 20 cm x 50 microm (i.d.) silica capillary at 25 degrees C and a constant voltage of +10 kV. Pharmacokinetics of gliclazide (80-mg tablet) in a diabetic patient were assayed by both HPLC and CE. Two hypoglycemic patients positive by HPLC analysis for unreported gliclazide and tolbutamide overdose were also screened by CE. Separation of six drugs (including the internal standard) was accomplished in 5 min plus 5 min rinsing. The between-day CV of the ratio of the areas of the sulfonylurea drugs to internal standard was <1% (n = 10). Linearity (r(2) > or =0.998) and recovery (> or =80%) were good for all sulfonylurea drugs tested. Pharmacokinetic curves for gliclazide by CE and HPLC were superimposable. CE analysis confirmed the HPLC diagnosis of surreptitious abuse of gliclazide and tolbutamide. CE is a useful tool in the clinical chemistry and toxicology laboratory for drug monitoring and pharmacokinetic investigations.

The Use of Time Step Simulations and Difference Equations (TSSADEQ) in Modeling Heparin Pharmacokinetics

A model in which the clearance of heparin requires the binding of heparin to a finite and regenerated pool of binding was constructed using time step simulations and difference equations (TSSADEQ). A simulation of a heparin i.v. bolus demonstrated a dose-dependent, triphasic pharmacokinetic curve with (1) an initial log-linear phase representing first-order association of heparin with binding sites, (2) an intermediate plateau phase representing constant regeneration of heparin binding sites, and (3) a terminal log-linear phase occurring when the quantity of regenerated sites exceeded the remaining heparin. Sensitivity analysis based on the literature produced estimates of the k at 1.39 to 2.77 h-1, the pool of binding sites of 50 units/kg, and the regeneration rate of 15 to 20 unit/kg/h--virtually identical to the empirically derived guidelines for the bolus size and infusion rate for unfractionated heparin. A pilot study of bolus dosing of unfractionated heparin in normal volunteers confirmed the model.

Fluorescence pharmacokinetics of Lutetium Texaphyrin (PCI-0123, Lu-Tex) in the skin and in healthy and tumoral hamster cheek-pouch mucosa

We have investigated the pharmacokinetics (PK) of Lutetium Texaphyrin (Lu-Tex), a second-generation photosensitizer, in the Syrian hamster cheek pouch early cancer model. Ten male hamsters, five with chemically induced early squamous cell cancer of the left cheek pouch, received an intracardiac injection of a 10 mg/ml Lu-Tex solution, resulting in a dose of 12 mg Lu-Tex per kg of bodyweight. The PK of the dye have been measured during the 24 h following the injection with an optical-fiber-based spectrofluorometer on the ventral skin, the healthy and the tumoral cheek-pouch mucosa. The Lu-Tex fluorescence is excited at 460 nm and detected around 740 nm. All the measurements yield very similar pharmacokinetic curves. The fluorescence intensity reaches a maximum between two and three hours after the injection and, at its maximum, it is consistently higher (up to 1.5 times) on the tumor than on the healthy mucosa. It remains smaller on the skin than on cheek-pouch mucosa. After 24 h, the Lu-Tex fluorescence is no longer detectable either on the skin, on the lesion or on the healthy mucosa. Moreover, Lu-Tex clearly displays a significant fluorescence selectivity between early carcinoma and healthy mucosa in this model. Furthermore, the inter-animal fluctuations of the fluorescence signal are small (±16% on the tumor-bearing mucosa). Eight-minute-long skin-irradiation tests have been performed 24 h after the injection of the Lu-Tex on the ventral skin of 16 additional animals with a solar simulator. No reaction is observed, either macroscopically or microscopically, which further demonstrates, as suggested by the fluorescence measurements, that this photosensitizer is significantly cleared from the skin after 24 h.

Sub-MIC concentrations of cefodizime interfere with various factors affecting bacterial virulence.

The molecular array of the outermost surface of bacteria and their physico-chemical characteristics modulate various functions which, when expressed in terms of the human environment, are generally known as factors of bacterial virulence. The present study investigated the ability of sub-MIC concentrations of cefodizime to interfere with the virulence factors of Escherichia coli. Bacterial adhesiveness to human epithelial cells was inhibited down to 1/32 x MIC of cefodizime, an antibiotic that is also capable of inducing the widespread production of filamentous forms at levels ranging from 1/2 to 1/8 x MIC. Given that this interfered with the correct evaluation of other virulence parameters, the study was extended to consider the effects of 1/16 to 1/128 x MIC. Sub-MIC concentrations of cefodizime inhibit haemagglutination, hydrophobicity and electrophoretic mobility, which are correlated with each other and provide clues relating to the physico-chemical characteristics of the outer surface. Cefodizime also reduces swarming. Phagocytosis was not affected but killing increased significantly. Oxidative bursts investigated by a chemiluminescence procedure were not modified. The interpolation of these pharmacodynamic findings with pharmacokinetic curves indicates that the effect of sub-MIC concentrations of cefodizime can prolong antimicrobial effects on virulence determinants up to 12 h after the antibiotic concentration has fallen below the MIC value.

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel.

Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. The following single-point model was selected as optimal: AUC carboplatin (min mg(-1) ml(-1)) = 418. c(2.5 h)(mg/ml) + 0.43 (min mg(-1) ml(-1)), where c(2.5 h) is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 +/- 1.6%) and precise (root mean square error = 10.1 +/- 1.5%). The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualize treatment.

The effect of folic acid on the drug metabolizing liver function in man with viral hepatitis

The investigations were carried out on 31 patients (16 men and 15 women, at the age of 20-50) with viral hepatitis. The all patients were divided at two groups. The first group (12 man) received usual treatment (diet, corsil), the second group (19 man) received in addition to the base treatment folic acid (5 mg per day, 10 days). It was found, that at patients with viral hepatitis was decreased the activity of monooxygenase system of liver. So, period of semielimination (T1/2) of antipyrine (AP) was greater in 1,4 time, area under the pharmacokinetic curve - 1,5 time and clearance was below by 39% than in volunteers (29 man). On day of treatment only by corsil, the rate of elimination of AP and clearance were increased by 34 and 31% (p < 0.05) respectively, T1/2 was decreased by 23% (p < 0.05) and area under the pharmacokinetic curve - 17 %. On 10 day of treatment by corsil with folic acid (5 mg per day), the rate of elimination of AP and clearance was increased by 43% (p < 0.05), area under the pharmacokinetic curve and T 1/2 were decreased by 30 and 33% (p < 0.05) respectively. The positive effect of folic acid in treatment of hepatitis at restoration period may be cause participating its derivatives in de novo nucleotide synthesis.

Bioanalysis of m-iodobenzylguanidine in plasma by high-performance liquid chromatography after derivatization with benzoin

A sensitive chromatographic assay has been developed for m-iodobenzylguanidine (MIBG) in human plasma based on the derivatization with benzoin. MIBG is first isolated from plasma using solid-phase extraction on a cyanopropyl-modified silica phase. After evaporation of the eluate, a fluorescent derivative is formed using benzoin. The derivative is analysed by reversed-phase liquid chromatography using a mixture 60% (v/v) acetonitrile, 30% (v/v) water and 10% (v/v) of the 0.5 M Tris buffer (pH 8.0) as the eluent and fluorescence detection at 320 nm for excitation and 435 nm for emission, respectively. In the evaluated concentration range (2–200 ng/ml) precisions ⩽10% and accuracies in between 90 and 100% have been found, with 2 ng/ml being the lower limit of quantification using a 0.5-ml plasma sample volume. The assay can also be used without the internal standard benzylguanidine. The assay was successfully used to obtain a pharmacokinetic curve of MIBG.

Influence of Sub-Minimum Inhibitory Concentrations of Cefodizime on the Phagocytosis, Intracellular Killing and Oxidative Bursts of Human Polymorphonuclear Leukocytes

It is generally recognized that sub-minimum inhibitory concentrations (sub-MICs) of antibiotics are still capable of interfering with some bacterial virulence parameters, thus facilitating host neutrophilic defenses such as phagocytosis, killing and oxidative bursts. This study investigated the interaction of Escherichia coli with these neutrophilic functions after pretreatment with various sub-MICs of cefodizime. E. coli exposed to 1/2 to 1/8 MICs of cefodizime showed the extensive production of long and very long filaments that interfere with the precise measurement of phagocytic and killing parameters. Our analysis was consequently extended to the activity of 1/16 to 1/64 MICs. The interesting finding was that, although phagocytosis was unaffected, killing was significantly increased in one strain at 1/16 MIC and in another at 1/32 MIC while in the last strain it was unaffected. Oxidative bursts were not modified by any of the sub-MICs. The knowledge that these sub-MICs are still effective in increasing bacteria killing, correlated with the pharmacokinetic curve of a common single dose of cefodizime 1 g i.m., showed that the killing effects of sub-MICs may last for as long as 12 h after the activity of the MIC value. This integrated information extends our knowledge of the ultimate efficacy of an antibiotic and provides further information for optimizing scheduling.

CYCLOSPOPORINE PHARMACOKINETICS IN HCV INFECTED UREMIC AND RENAL TRANSPLANT PATIENTS

349 We sought to determine whether there are alterations in cyclosporine A (CsA) pharmacokinetics in patients chronically infected with hepatitis C virus (HCV) without clinical or laboratory (LFTs) evidence of hepatic damage. The presence of anti-HCV antibodies was detected by a third generation ELISA and viremia by PCR. Thirteen determinations of CsA serum level were performed by fluorescence polarization immunoassay with monoclonal antibodies in a 12 h pharmacokinetic curve. In the first part of the study a 8 mg/kg oral dose of CsA microemulsion was given to 11 anti-HCV+ (cases) and 11 paired anti-HCV- (controls) patients on chronic hemodialysis selected from the kidney transplant waiting list. The AUC0-12 was 42% higher (13,322±5, 109 ng.h−1/ml) in cases as compared to controls (9,350±3,325; p=0.051). Comparing those patients with (n=7) and without (n=15) viremia the difference rose to 71% (p<0.01). These results were determined by a better absorption (Cmax 54% higher; p<0.04) and a 41% slower oral clearance (p<0.02). In the evaluations performed in kidney transplant recipients, 23 consecutive patients were studied at the 15th post-transplant day using the prescribed oral dose of CsA microemulsion. The AUC0-12 corrected for CsA dose was 37% bigger (p=0.18) among cases (n=10) than controls (n=13). Analyzing the viremic patients (n=6), the difference rose to 47% (p<0.01). This increment resulted from a better absorption (Cmax 58% higher; p<0.001) and a 32% slower oral clearance (p<0.01). In conclusion, the present studies demonstrated that HCV chronically infected patients, particularly the viremic individuals, have a higher exposure to oral CsA. These results may have relevant clinical implications in the CsA dose adjustments in HCV infected renal transplant patients.

Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients.

To assess the relationship between indinavir-associated urological complaints and indinavir plasma concentrations. Case series, comparing indinavir plasma concentrations in cases with average concentrations in a control group. Patients taking 800 mg indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of indinavir plasma concentrations from a control group of 14 patients taking 800 mg indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of indinavir. Seventeen patients (five women) were enrolled and the indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with indinavir concentrations above the upper 95% limit, indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months. Urological complications occurring during indinavir treatment were associated with elevated indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.

Quantitative capillary electrophoresis–ion-trap mass spectrometry determination of methylphenidate in human urine

A quantitative capillary electrophoresis–mass spectrometry method has been demonstrated for the determination of methylphenidate in human urine over a dynamic range of 640. The samples were prepared by liquid–liquid extraction using 4 ml of human urine. The extracts were analyzed using a Finnigan LCQ ion-trap mass spectrometer in a two-event, positive-ion full-scan MS and tandem MS selected reaction monitoring mode. The lower level of quantitation was determined to be 1.5 ng/ml methylphenidate in human urine. The intra-assay precision had a relative standard deviation less than 6.8%. The intra-assay accuracy was less than ±14.7% bias from the nominal concentration for the full-scan MS analysis, and less than ±26.5% bias for the tandem MS analysis. Six incurred human urine samples containing methylphenidate were analyzed and a simple pharmacokinetic curve is presented.

Clinical Pharmacology of Recombinant Human Follicle-Stimulating Hormone. II. Single Doses and Steady State Pharmacokinetics

Objective: To assess the single-dose pharmacokinetics of a recombinant human FSH preparation (Gonal-F; Laboratoires Serono, Aubonne, Switzerland), administered by IV, IM, and SC routes and its pharmacokinetics at steady state after multiple dosing by the SC route. Design: Twelve healthy down-regulated female volunteers received in random order three single doses of recombinant human FSH (150 IU IV, IM, and SC), with each administration separated by 1 week. The volunteers then received multiple recombinant human FSH doses by the SC route (150 IU one time per day) for 7 days. Follicle-stimulating hormone concentrations were measured by an immunoradiometric assay and an in vitro granulosa cell aromatase bioassay. Result(s): After a single administration, the pharmacokinetics of recombinant human FSH were well described by a two-compartment model after IV administration and by a one-compartment model with first order absorption after IM or SC administration. The mean total clearance of FSH was approximately 0.6 L/h, and renal clearance accounted for one tenth of the total elimination after IV administration. The distribution half-life was close to 2 hours. The terminal half-life was nearly 1 day when estimated either by modeling the IV data set or from analysis of the terminal phase of the steady state pharmacokinetic curve or from the time taken to reach steady state after repeated SC administrations. After single IM and SC injection, two thirds of the administered dose was available systemically. The cumulation factor for repeated SC administration was approximately 3 when steady state was reached. The in vitro bioassay data confirmed these estimations. The temporal evolution of the bioassay:immunoassay ratio suggests either metabolic selection or activation of recombinant human FSH toward forms with greater in vitro bioactivity. Conclusion(s): The estimation of the elimination half-life of approximately 1 day indicates that the maximal effect of a given dose of recombinant human FSH administered daily cannot be observed until 3 to 4 days of repeated administration. This indicates that, on a pure pharmacokinetic basis, physicians should wait at least 4 days to assess the efficacy of a given dose of recombinant human FSH and that they should not modify dosage too frequently.

Limited Sampling Models for the Pharmacokinetics of Docetaxel

Limited sampling models for estimation of the docetaxel area under the plasma concentration versus time curve (AUC) and the duration above a threshold concentration of 100 µg/L (T > 100) from a limited number of plasma concentration determinations are desired for population kinetic studies. We have developed and validated models using 24 pharmacokinetic curves of patients participating in a phase II study of docetaxel (100 mg/m2) administered as a 1-hour infusion. Two models were selected as optimal: $${\rm AUC}\;({\rm mg/L} \cdot {\rm h}) = 0.498({\rm h}) \cdot {{\rm C}_{\rm 30 min}}\;({\rm mg/L}) + 11.2({\rm h}) \cdot {{\rm C}_{\rm 2h}}\;({\rm mg/L}) + 0.758\;({\rm mg/L} \cdot {\rm h}),$$ and for the time above a concentration of 100 µg/L $${\rm T} > 100({\rm h}) = 5.28\;({\rm h}) \cdot {\rm C}_{\rm 2h}\;({\rm mg/L}) + 22.3\;({\rm h}) \cdot {\rm C}_{\rm 4h}\;({\rm mg/L}) + 0.276\;({\rm h})$$ where C30min, C2h and C4h are the plasma concentrations (µg/L) of docetaxel at respectively 30 minutes, 2 hours and 4 hours after the start of a 1-hour infusion. The models proved to be unbiased [MPE% = 4.6% (± 4%) and −3.9% (± 3%), respectively] and precise [RMSE% = 15.1% (± 3%) and 12.7% (± 3%), respectively].

Comparative Pharmacokinetics of New Theophylline Preparations as Egifilin® 200 mg and 400 mg Retard Tablets After Single Dose in Healthy Volunteers

Pharmacokinetic properties of Egifilin® retard tablets (containing 200 or 400 mg of theophylline, EGIS Pharmaceuticals Ltd., Budapest, Hungary) were investigated in 12 healthy volunteers (six women, six men). Pharmacokinetic analysis was performed according to a one-compartment open model. The retard nature of both 200 and 400 mg tablets could be demonstrated. Comparison of the pharmacokinetic curves of women and men indicated that there was no sex difference in the pharmacokinetics of two retard tablets.Egifilin retard tablets ensured plasma levels for almost 30 hr after single drug intake with an extremely long retard plateau between 6 and 30 hr. For study purposes, an improved rapid HPLC-UV analytical method (less than 3.5 min chromatogram) has been elaborated for the determination of theophylline in human plasma. The range of the calibration is 0.6–18 μg/ml.