Drug Clearance Values Research Articles

Can In Vitro-In Vivo Extrapolation Be Successful? Recognizing the Incorrect Clearance Assumptions.

For a number of years, our laboratory has been investigating the underlying reasons for the published poor in vitro-in vivo extrapolation (IVIVE) predictability of human clearance both from a theoretical and from an experimental perspective. Here, we critically examine clearance concepts and commonly employed IVIVE approaches, concluding that there is no theoretical reason that IVIVE should work, just as it does not. Our analysis, however, has identified 10 misconceptions and/or poorly understood aspects of clearance that are listed in the Conclusion section of this manuscript. Chief among these are that all published human drug clearance values are arterial clearances-clearance calculated as organ blood flow multiplied by the extraction ratio is the arterial clearance of the organ of elimination (and not the published drug clearance value)-and that the well-stirred model equation taught in all pharmacokinetic courses that relates organ blood flow, fraction unbound in blood, and intrinsic clearance has no validity. We further list 10 conclusions relating to the IVIVE process. The primary IVIVE-related conclusions are that the intrinsic clearance value determined from an in vitro incubation is an arterial intrinsic clearance, there is no theoretical basis upon which an arterial intrinsic clearance can be related to a whole-body arterial clearance to accomplish IVIVE, there are no published data demonstrating that in vitro intrinsic metabolic clearance can predict in vivo organ clearance as IVIVE assumes, and the scientific basis for the hypothesized albumin-mediated hepatic uptake phenomenon is invalid. We further propose three IVIVE process recommendations.

Population Pharmacokinetic Modeling of Vancomycin in Thai Patients With Heterogeneous and Unstable Renal Function.

Vancomycin is widely used to treat gram-positive bacterial infections. However, given significant interpatient variability in its pharmacokinetics, maintaining plasma concentrations is difficult within its characteristically narrow therapeutic window. This is especially challenging in patients with unstable renal function. Thus, the aim of this study was to develop a population pharmacokinetic model for vancomycin that is suitable for Thai patients with variable renal functions, including those with unstable renal function. Data from 213 patients, including 564 blood samples, were retrospectively collected; approximately 70% patients exhibited unstable renal function during vancomycin treatment. The model building group was randomly assigned 108 patients and the remaining 33 patients comprised the validation group. A population pharmacokinetic model was developed that incorporated drug clearance (CL) as a function of time-varying creatine clearance (CrCL). The predictive ability of the resulting population model was evaluated using the validation data set, including its ability to forecast serum concentrations within a Bayesian feedback algorithm. A 2-compartment model with drug CL values that changed with time-varying CrCL adequately described vancomycin pharmacokinetics in the evaluated heterogeneous patient population with unstable renal function. Vancomycin CL was related to time-varying CrCL as follows: CL (t) = 0.11 + 0.021 × CrCL (t) (CrCL <120 mL/min. Using the population model, Bayesian estimation with at least one measured serum concentration resulted in a forecasting error of small bias (-2.4%) and adequate precision (31.5%). In hospitals with a high incidence of unstable renal function, incorporating time-varying CrCL with Bayesian estimation and at least one measured drug concentration, along with frequent CrCL monitoring, improves the predictive performance of therapeutic drug monitoring of vancomycin.

Prediction of Drug Clearance and Drug-Drug Interactions in Microscale Cultures of Human Hepatocytes

Accurate prediction of in vivo hepatic drug clearance using in vitro assays is important to properly estimate clinical dosing regimens. Clearance of low-turnover compounds is especially difficult to predict using short-lived suspensions of unpooled primary human hepatocytes (PHHs) and functionally declining PHH monolayers. Micropatterned cocultures (MPCCs) of PHHs and 3T3-J2 fibroblasts have been shown previously to display major liver functions for several weeks in vitro. In this study, we first characterized long-term activities of major cytochrome P450 enzymes in MPCCs created from unpooled cryopreserved PHH donors. MPCCs were then used to predict the clearance of 26 drugs that exhibit a wide range of turnover rates in vivo (0.05-19.5 ml/min per kilogram). MPCCs predicted 73, 92, and 96% of drug clearance values for all tested drugs within 2-fold, 3-fold, and 4-fold of in vivo values, respectively. There was good correlation (R(2) = 0.94, slope = 1.05) of predictions between the two PHH donors. On the other hand, suspension hepatocytes and conventional monolayers created from the same donor had significantly reduced predictive capacity (i.e., 30-50% clearance values within 4-fold of in vivo), and were not able to metabolize several drugs. Finally, we modulated drug clearance in MPCCs by inducing or inhibiting P450s. Rifampin-mediated CYP3A4 induction increased midazolam clearance by 73%, while CYP3A4 inhibition with ritonavir decreased midazolam clearance by 79%. Similarly, quinidine-mediated CYP2D6 inhibition reduced clearance of dextromethorphan and desipramine by 71 and 22%, respectively. In conclusion, MPCCs created using cryopreserved unpooled PHHs can be used for drug clearance predictions and to model drug-drug interactions.

Evaluation of a Liver Microfluidic Biochip to Predict In Vivo Clearances of Seven Drugs in Rats

AbstractWe investigated metabolic clearances of phenacetin, midazolam, propranolol, paracetamol, tolbutamide, caffeine, and dextromethorphan by primary rat hepatocytes cultivated in microfluidic biochips. The levels of mRNA of the HNF4α, PXR, AHR, CYP3A1, and CYP1A2 genes were enhanced in the biochip cultures when compared with postextraction levels. We measured a high and rapid adsorption on the biochip walls and inside the circuit for dextromethorphan and midazolam, a moderate adsorption for phenacetin and propranolol, and a low adsorption for caffeine, tolbutamide, and paracetamol. Drug biotransformations were demonstrated by the formations of specific metabolites such as paraxanthyne (caffeine), paracetamol (phenacetin), 1-OH midazolam (midazolam), paracetamol sulfate (paracetamol and phenacetin), and dextrorphan (dextromethorphan). We used a pharmacokinetic model to estimate the adsorption and in vitro intrinsic drug clearance values. We calculated in vitro intrinsic clearance values of 0.5, 3, 12.5, 83, 100, 160, and 900 μL/min per 106 cells for the tolbutamide, caffeine, paracetamol, dextromethorphan, phenacetin, midazolam, and propranolol, respectively. A second model describing the liver as a well-stirred compartment predicted in vivo hepatic clearances of 0.1, 13.8, 30, 44.1, 61, 72, 85, and 61 mL/min per kg of body mass for the tolbutamide, caffeine, paracetamol, midazolam, dextromethorphan, phenacetin, and propranolol, respectively. These values appeared consistent with previously reported data. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:706–718, 2014

Investigating the pharmacokinetics and dosing of anticancer drugs in infants and young children.

10033 Background: Dosing regimens for anticancer drugs administered to infants and young children frequently differ between tumour types and protocols, with dosing based on body weight commonly implicated. We have recently highlighted a reduced exposure to 13-cis-retinoic acid in neuroblastoma patients &lt;12kg dosed on body weight (Clin Cancer Res19:469-79,2013). Given the toxicity observed with many chemotherapeutics, it is appropriate to establish a pharmacological basis for dose adjustments implemented in younger patients. Methods: The pharmacokinetics of cyclophosphamide (CPA), actinomycin D (Act D), carboplatin and etoposide were investigated in children aged 0-6, 6-12 and 12-24 months. CPA was administered i.v. at a dose of 100-1,500 mg/m2, with infusion times up to 1.5h, Act D as a bolus i.v. infusion of 0.4-1.5mg/m2, carboplatin as an i.v. dose of 3.8-30mg/kg over 1-4h and etoposide as an i.v. dose of 3.5-14mg/kg over 1-6h. Eighty-six children were studied at 14 centres, with PK sampling carried out over 24h for CPA and Act D, 3h for carboplatin and up to 6h for etoposide. Plasma concentrations of CPA, Act D and etoposide were determined by LC-MS analysis, with carboplatin concentrations determined in plasma ultrafiltrate by AAS. PK parameters were calculated using WinNonlin or previously used PK models as appropriate. Results: Clearance values normalized to body weight ranged from 0.5-7.7 ml/min/kg for CPA, 1.7-17.4 for Act D, 1.6-10.5 for carboplatin and 0.2-1.7 for etoposide. No significant differences in normalized clearance were observed between the defined age cohorts of 0-6, 6-12 and 12-24 months and the data do not indicate clear differences in drug handling in infants and young children. However, when normalized clearance values were compared to data from older children, a greater degree of inter-patient variation was observed in patients &lt;2 years than in children &gt;2 years for all drugs. Conclusions: While normalized clearance values for the drugs studied do not support reduced dosing approaches, data suggest that individual drug clearance values may be more difficult to predict in younger patients. Further studies involving additional anticancer drugs may allow more rationale approaches to dosing. Clinical trial information: NCT00897871.

Drug Dosing During Continuous Renal Replacement Therapies

Continuous renal replacement therapies (CRRT) are used to manage fluid overload and/or renal failure. The continuous nature of the fluid and solute removal has less impact on hemodynamic variables in critically ill patients, making CRRT preferred over intermittent hemodialysis for some patients in the intensive care arena. The impact of CRRT on drug removal is variable depending on the CRRT modality, the ultrafiltrate and dialysate flow rates, the filter, and the patient's residual renal function; all of these may change from patient to patient or even in the same patient depending on the clinical status. However, CRRT modalities are generally more efficient than intermittent hemodialysis at drug removal, in some cases approximating or even exceeding normal renal function, resulting in a significant risk of subtherapeutic dosing if conventional hemodialysis dosing recommendations are followed. This annotated bibliography provides a summary of publications analyzing drug removal during CRRT, including CRRT settings and drug clearance values found in each study. Caution is warranted as findings from one study may not be generalizable to all patients due to the many factors that influence drug removal. Serum drug concentrations should be monitored when available, and patient clinical status is exceedingly important for following expected and unexpected responses to drug therapies. Reviews on general drug dosing calculations in CRRT are available elsewhere.

Experience with fixed-bred charcoal haemoperfusion in the treatment of severe drug intoxication.

Fifteen patients who were severely poisoned with either hypnotic drugs or salicylate were treated by charcoal haemoperfusion. The device contained 100g of activated charcoal immobilised by fixation to a polyester film. Two patients showed no response and eventually died. The remainder showed marked lightening of coma and recovered uneventfully. Complications of platelet loss and, in one patient, fibrinolysis were observed, but these had no serious consequences. No significant biochemical disturbances occurred with the exception of one patient who presented with hypocalcaemia and required intravenous calcium throughout the treatment. Drug clearance values were comparable with those obtained with columns containing 300 g of acrylic polymer coated charcoal.

Adsorptive capacities of hemoperfusion devices in clinical use.

Five different hemoperfusion devices have been used in the treatment of patients, intoxicated with barbiturates. The changes in drug clearance values which occurred during hemoperfusion varied according to the device used. Even after very long periods of hemoperfusion, however, drug clearance values never fell to zero. Using data collected from comparable cases, it has been shown that the rate of uptake of drug from the blood is independent of the amount of adsorbent in the columns, those containing 100 gm charcoal having the same efficiency as the conventional 300 gm. The prime factor which determines the rate of drug uptake has been shown to be the arterial plasma drug concentrations. Other factors, such as the deposition of cellular debris and proteins as hemoperfusion progresses, are also thought to influence the efficiency of drug removal.