Ronald J. Sawchuk

Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: gentamicin in burn patients.

A general approach to the establishment of dosing regimens for drug administration by multiple intravenous infusions is presented. The method is applicable where the elimination kinetics are first order and can be represented by a one-compartment open model. The approach utilizes serum concentration-time data obtained during any dosing interval for the calculation of the apparent distribution volume and the half-life in individual patients. These values are then used to individualize the dosing regimen where it is required to maintain serum concentrations of the drug within a desired range. Estimation of kinetic parameters for gentamicin in burn patients with normal or only slightly reduced renal function demonstrates a relatively constant distribution volume of 0.25 ± 0.086 liter/kg (mean ±sd)but a relatively variable half-life of 2.1 ± 1.3 hr. This finding supports the view that gentamicin regimens should be individualized even in patients with essentially normal renal function.

Application of Microdialysis in Pharmacokinetic Studies

The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses various aspects of the technique with regard to its use in pharmacokinetic studies, such as: quantitation of the microdialysis probe relative recovery, interfacing the sampling technique with analytical instrumentation, and consideration of repeated procedures using the microdialysis probe. The remainder of the review is devoted to a survey of the recent literature concerning pharmacokinetic studies that apply the microdialysis sampling technique. While the majority of the pharmacokinetic studies that have utilized microdialysis have been done in the central nervous system, a growing number of applications are being found in a variety of peripheral tissue types, e.g. skin, muscle, adipose, eye, lung, liver, and blood, and these are considered as well. Given the rising interest in this technique, and the ongoing attempts to adapt it to pharmacokinetic studies, it is clear that microdialysis sampling will have an important place in studying drug disposition and metabolism.

Kinetic model for gentamicin dosing with the use of individual patient parameters

Multiple‐infusion dosing regimens for gentamicin were established for 84 patients with the use of individually calculated values of elimination kinetic parameters. Serum level‐time data obtained after a single infusion were used to determine the patients gentamicin half‐life (t½) and distribution volume. Patients with serum creatinine (Cr) <1.2 mg per 100 ml had t½s (mean, 2.25 hr) and total body clearances (mean, 0.082 L/hr/kg) significantly different from those with Cr ≥1.2 mg/100 ml (means, 5.3 and 0.039, respectively). Distribution volumes were not significantly different (means, 0.22 and 0.21 L/kg, respectively). Calculations of dosing intervals and infusion rates, based on each patients kinetic parameters and desired steady‐state peaks and nadirs, assumed a one‐compartment model with first‐order elimination and 1‐hr constant‐rate input at fixed intervals. Follow‐up steady‐state peak and nadir levels were measured in 63 of the regimens. Differences between predicted and measured peak levels averaged ‐0.05 µg/ml with 60% of the measured values falling within 1 µg/ml of that predicted. Predicted‐measured nadir differences averaged −0.62 µg/ml (significantly different from zero) indicating slight bias in the model. Fifty‐six percent of these nadirs were within 1 µg/ml of that predicted.

AAPS-FDA workshop white paper: Microdialysis principles, application, and regulatory perspectives

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (μD) is the only tool available that explicitly provides data on the extracellular space. Although μD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of μD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of μD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on μD as a tool in drug research and development.

Microdialysis calibration using retrodialysis and zero-net flux: application to a study of the distribution of zidovudine to rabbit cerebrospinal fluid and thalamus.

A retrodialysis (RD) method for the real-time calibration of on-line microdialysis (MD) procedures was investigated in vitro and in vivo. Calibration by retrodialysis was simultaneously validated through the use of a zero-net flux (ZNF) method, which assumes directional independence of diffusion of the solute. In RD, a calibrator with dialysance (PeA; effective permeability–surface area product) similar to that of the compound of interest is introduced into the perfusate. If the calibrator is suitable, its loss from the perfusate during RD is identical to the recovery of the solute of interest determined simultaneously by normal MD. Two antiviral nucleosides (AZT and AZdU) which differ structurally by only a methylene group were utilized as solute and calibrator, respectively. Both nucleosides exhibited similar recovery and loss at flow rates of 0.5 to 5 (µL/min in vitro, indicating a similar PeA product in this flow domain. Furthermore, both compounds showed similar loss into the lateral ventricle or thalamus of rabbits (n = 4) during RD at a flow rate of 1 µL/min for 6 hr. The relative loss decreased rapidly within the first hour, reaching a relatively stable value after 2 hr. The significant reduction in the loss of AZdU and AZT in vivo compared with that in vitro likely results from a lower diffusion coefficient in tissue. The distribution of AZT between plasma and cerebrospinal fluid (CSF) in the ventricle and extracellular fluid (ECF) in thalamus was determined at steady state using calibration by RD and ZNF simultaneously. The relative loss of AZdU during continuous RD was not significantly different from the recovery of AZT determined by ZNF in the same animal. Since RD may allow for continuous monitoring of microdialysis recovery in real time, it may offer an advantage over the ZNF method of system calibration. The steady-state Ccsf/Cp and Cecf/Cp ratios for AZT in this study were 0.26 ± 0.08 and 0.18 ± 0.08. That these ratios are much less than unity suggests that carrier-mediated transport of AZT exists in the brain-to-plasma direction.

Human pharmacokinetics of the antiviral drug DHPG

The pharmacokinetics of the antiviral drug 9‐[2‐hydroxy‐l‐(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis. Biexponential decay with a mean distribution t1/2 of 0.23 hours and terminal t1/2 of 2.53 hours was observed. Total clearance correlated well with and exceeded creatinine clearance by a factor of 2.4. Mean volume of the central compartment was 15.26 L/1.73 m2 and the volume of distribution at steady state was 32.8 L/1.73 m2. Peak (model predicted) and trough plasma concentrations were 4.75 to 6.20 μg/ml and <0.25 to 0.63 fJig/ml, respectively, in patients receiving 2.5 mg/kg. Peak concentrations are well above those needed to inhibit HCMV at the 50% level (ID50) and troughs are near this ID50. Cerebrospinal fluid concentrations of DHPG indicate a penetration of 24% to 67%. No accumulation of DHPG was apparent in these patients. However, dosage reduction is necessary in renal insufficiency. Neutropenia occurred in one patient. The plasma concentration profile of DHPG suggests potential beneficial activity against HCMV.

Pharmacokinetics of vancomycin: observations in 28 patients and dosage recommendations.

Studies of the pharmacokinetics of vancomycin were conducted in a group of 28 patients with serious staphylococcal infection. Serum specimens were collected before and on 11 occasions after vancomycin administration. Serum concentration time data were fitted to a biexponential equation, using nonlinear regression analysis. A prolonged distribution phase with a half-life of 0.5 +/- 0.3 h (standard deviation) and a central component volume of 9.0 +/- 4.0 liters were demonstrated. Wide interpatient variation was observed in the terminal half-life which ranged from 3 to 13 h (mean, 6 h) and in the distribution volume which ranged from 14 to 111 liters (mean, 39 liters). A correlation of 0.45 (Pearson product moment correlation coefficient) was found between vancomycin clearance and creatinine clearance. Multiple regression analyses demonstrated that 50% of the variance (R2) in the terminal half-life and vancomycin clearance could be explained on the basis of renal function, volume of distribution, age, weight, and sex. These observations suggest that adults with normal renal function should receive an initial dosage of 6.5 to 8 mg of vancomycin per kg intravenously over 1 h every 6 to 12 h. After 24 h, and through the period of therapy, trough and peak serum vancomycin concentrations should be monitored, and the dose and dosage interval should be changed to produce the desired peak (30 to 40 micrograms/ml) and trough (5 to 10 micrograms/ml) levels.

Increased dosage requirements of gentamicin in burn patients.

In 14 burn patients treated for serious Gram-negative infections, the use of the previously recommended gentamicin dose of 5 mg/kg/day was found to result in subtherapeutic serum concentrations (peak concentration less than 4 mg/L). The gentamicin half-life was found to be unusually short especially in the younger burn patients. Because of this shorter half-life the dosage interval was decreased to 4 hours to prevent extended periods of subtherapeutic serum concentrations. In addition, the daily dose of gentamicin was increased to achieve therapeutic peak concentration. Individualizing each patients gentamicin regimen was thought to be instrumental in the favorable response of two patients with Pseudomonas ecthyma gangrenosum. The results of this study would strongly support the measurement of serum gentamicin levels in all burn patients with life-threatening infection. The gentamicin dosage regimen should then be individualized for each patient to provide optimal peak concentrations. In addition, patients demonstrating a short drug half-life may require a decreased dosage interval to prevent prolonged periods of sub-therapeutic concentrations.

Analysis of Zidovudine Distribution to Specific Regions in Rabbit Brain Using Microdialysis

The distribution of zidovudine (3′-azido-3′-deoxythymidine; AZT) into two regions of rabbit brain was investigated in crossover using microdialysis. Six rabbits had guide cannulas surgically implanted in the lateral ventricle and thalamus by stereotaxic placement. After recovery, microdialysis probes were positioned and i.v. bolus doses of 5, 10, 20, and 30 mg/kg were administered to each animal over a period of 2 weeks. Blood was drawn via a marginal ear vein catheter for 8 hr. Brain dialysate was collected at 3 µl/min from ventricle and thalamus dialysis probes every 10 min. Simulated cerebrospinal fluid (CSF), to which 3′-azido-2′,3′-dideoxyuridine (AZdU) was added, was used as perfusate. AZdU loss, which was measured during simultaneous retrodialysis, served as a marker for in vivo recovery of AZT. AZT concentrations in plasma, as well as in ventricle and thalamus dialysate, were determined using a sensitive HPLC assay, and AZdU was simultaneously analyzed in the dialysates. Calculation of in vivo recovery of AZT was based on loss of AZdU from the perfusate during retrodialysis and was used to estimate the concentration of drug at both sites in the brain. In vitro loss of AZdU and recovery of AZT showed good agreement, demonstrating a bivariate regression slope of 0.99. The half-lives and AUCs (normalized to dose) achieved in the plasma, ventricle, or thalamus were not significantly different for the four doses. The AUC ratios, which represent the ratio of clearances into and from the CNS, were not significantly different among the doses studied (AUCv/AUCp range, 0.16–0.19; AUCt/AUCp range, 0.05–0.09), providing further evidence that the kinetics of distribution into the thalamus and CSF are linear. The results also demonstrate that the time-averaged concentrations of AZT in thalamus ECF are about half of those in the CSF.

In vitro and in vivo evaluation of transdermal iontophoretic delivery of hydromorphone

Abstract The narcotic analgesic, hydromorphone, was delivered by constant-current iontophoresis from aqueous solution through excised pig and human skin and from a hydrogel formulation into domestic pigs. The delivery rate per unit current was found to be similar for both pig and human skin, with a value of 1.1 mg h−1 mA−1, even though the passive fluxes differed by a factor of six. The in vitro delivery rate through pig skin at a current density of 125 μA/cm2 was found to be independent of the concentration of hydromorphone in the donor solution over the range from 0.01 M to 0.8 M. No correlation was observed between the initial passive hydromorphone delivery rate through pig skin and the steady-state rate during iontophoresis. In addition, in vivo delivery of hydromorphone into domestic pigs was studied at currents of up to 1.2 mA for 12 hours. Delivery rates were determined from plasma hydromorphone concentrations and from residual drug analysis of spent patches. The delivery rate per unit current determined from the plasma concentration and residual assay data were 1.9 and 1.2 mgh−1 mA−1, respectively.