G. Richard Granneman

Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions

SummaryThis article reviews the information available to assist pharmacokineticists in the prediction of metabolic drug interactions. Significant advances in this area have been made in the last decade, permitting the identification in early drug development of dominant cytochrome P450 (CYP) isoform(s) metabolising a particular drug as well as the ability of a drug to inhibit a specific CYP isoform. The major isoforms involved in human drug metabolism are CYP3A, CYP2D6, CYP2C, CYP1A2 and CYP2E1. Often patients are taking multiple concurrent medications, and thus an assessment of potential drug-drug interactions is imperative.A database containing information about the clearance routes for over 300 drugs from multiple therapeutic classes, including analgesics, anti-infectives, psychotropics, anticonvulsants, cancer chemotherapeutics, gastrointestinal agents, cardiovascular agents and others, was constructed to assist in the semiquantitative prediction of the magnitude of potential interactions with drugs under development. With knowledge of the in vitro inhibition constant of a drug (Ki) for a particular CYP isoform, it is theoretically possible to assess the likelihood of interactions for a drug cleared through CYP-mediated metabolism. For many agents, the CYP isoform involved in metabolism has not been identified and there is substantial uncertainty given the current knowledge base.The mathematical concepts for prediction based on competitive enzyme inhibition are reviewed in this article. These relationships become more complex if the inhibition is of a mixed competitive/noncompetitive nature. Sources of uncertainty and inaccuracy in predicting the magnitude of in vivo inhibition includes the nature and design of in vitro experiments to determine Ki, inhibitor concentration in the hepatic cytosol compared with that in plasma, prehepatic metabolism, presence of active metabolites and enzyme induction. The accurate prospective prediction of drug interactions requires rigorous attention to the details of the in vitro results, and detailed information about the pharmacokinetics and metabolism of the inhibitor and inhibited drug.With the discussion of principles and accompanying tabulation of literature data concerning the clearance of various drugs, a framework for reasonable semiquantitative predictions is offered in this article.

Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients

ABSTRACT The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly Cmin, than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC12), Cpredose, and Cmin by 46, 70, and 141%, respectively. The increase in lopinavir Cmax (33%,) did not reach statistical significance. Ritonavir AUC12, Cmax, Cpredose, and Cmin values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.

Pharmacokinetic interaction between ritonavir and clarithromycin

Because ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, and clarithromycin, a macrolide antibiotic used in the treatment of disseminated infection caused by Mycobacterium avium complex, are likely to be administered concurrently for treatment of patients with HIV and acquired immunodeficiency syndrome (AIDS), the drug interaction potential of these 2 agents was evaluated. Both clarithromycin and ritonavir are metabolized to a significant extent through cytochrome P450‐mediated biotransformation and are potential inhibitors of these enzymes.

Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable

Levothyroxine (LT4) has a narrow therapeutic index. Consequently, precise standards for assessing the bioequivalence of different LT4 products are vital. We examined the methodology that the Food and Drug Administration (FDA) recommends for comparing the bioavailability of LT4 products, as well as three modifications to correct for endogenous, thyroxine (T4) levels, to determine if the methodology could distinguish LT4 products that differ by 12.5%, 25%, or 33%. With no baseline correction for the endogenous T4 pool, differences in administered LT4 doses that differed by 25%-33% could not be detected (450 microg and 400 microg doses versus 600 microg dose, respectively). The three mathematical correction methods could distinguish the doses that differed by 25% and 33%. None of the correction methods could distinguish dosage strengths that differed by 12.5% (450 microg versus 400 microg). Dose differences within this range are known to result in clinically relevant differences in safety and effectiveness. Methods of analysis of bioequivalence data that do not consider endogenous T4 concentrations confound accurate quantitation and interpretation of LT4 bioavailability. As a result, products inappropriately deemed bioequivalent may put patients at risk for iatrogenic hyperthyroidism or hypothyroidism. More precise methods for defining bioequivalence are required in order to ensure that LT4 products accepted as bioequivalent will perform equivalently in patients without the need for further monitoring and retitration of their dose.

Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy

The availability of an intravenous formulation now makes possible rapid administration of valproate (VPA) loading doses, but estimates of key VPA pharmacokinetic parameters in patients have limited the use of this approach. VPA disposition was characterized in 112 epilepsy patients, with or without enzyme inducing comedications, randomized to either 3.0 or 1.5mg/kg/min infusions of valproate sodium injection. Maximum dose was </=15mg/kg per infusion. Total and unbound plasma VPA concentrations were determined from blood samples obtained prior to and for 6h following the infusion. Analyses of covariance assessed the effect of induction, weight, age, gender, albumin, creatinine, and infusion rate on pharmacokinetics. Maximum total and unbound VPA concentrations were 94 and 14mg/l, respectively. Total concentration fell below 50mg/l within 3h in induced and 6h in uninduced patients. VPA unbound fraction decreased from 15% at maximum concentration to 9% at 45mg/l. The mean (S.D.) distribution volume was 0.21 (0.044)l/kg. Induction status, albumin concentration, and infusion rate significantly affected pharmacokinetics. Measurement of unbound VPA may be useful when alterations in binding are suspected. Infusions up to 3mg/kg/min produce predictable total VPA concentrations when induction status and albumin levels are considered.

Effect of Zileuton on Theophylline Pharmacokinetics

SummaryIn controlled trials involving asthma patients, zileuton — a selective 5-lipoxygenase inhibitor — has significantly improved pulmonary function and reduced symptoms. Since theophylline is frequently prescribed for asthma, we designed a placebo-controlled randomised crossover trial to examine the influence of zileuton on theophylline pharmacokinetics.16 healthy adult males were given theophylline (Slo-Phyllin® ) 200mg 4 times daily for 5 days and either zileuton 800mg twice daily or a matching placebo. After a 15-day washout period, theophylline was resumed and the other study drugs reversed. During coadministration with zileuton, mean peak theophylline levels rose from 12.14 to 20.99 mg/L (p < 0.001), while the apparent plasma clearance dropped from 3.74 to 1.91 L/h (p < 0.001). The time to the peak theophylline concentration was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. 14 volunteers reported 44 mild or moderately severe adverse events, possibly or probably related to coadministration of zileuton, and 8 volunteers reported 8 such events with placebo coadministration. Three volunteers receiving theophylline plus zileuton withdrew from the trial prematurely.Thus, a pharmacokinetic interaction that may produce theophylline toxicity exists between zileuton and theophylline. Accordingly, theophylline dosages in patients receiving zileuton should be adjusted to maintain levels within the therapeutic range. Upon initiation of zileuton, the typical asthma patient may require dosage reductions of one-half, and monitoring of plasma theophylline concentrations is recommended.

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction.

Pharmacokinetics of sertindole in healthy young and elderly male and female subjects

The pharmacokinetic disposition of oral sertindole, a new selective antipsychotic compound, in young and elderly male and female subjects was investigated.

Pharmacokinetics of Valproate After Multiple‐Dose Oral and Intravenous Infusion Administration: Gastrointestinal‐Related Diurnal Variation

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady‐state pharmacokinetics of valproate after multiple 250‐mg oral and intravenous infusion doses after an intravenous 750‐mg loading dose. Multiple blood samples were collected throughout each 168‐hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within‐regimen comparisons indicated statistically significant differences for mean steady‐state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration‐versus‐time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed‐release tablet preparation. Between‐regimen steady‐state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax (Tmax), Cmax, Cmin, AUC, and total body clearance for respective day‐4 dosing intervals, but not for the entire day 4, except for Cmin and Tmax. Mean elimination rate constant and half‐life did not significantly differ between the regimens. The regimens were bio‐equivalent at steady state, as assessed by 90% confidence intervals (two one‐sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation {(Cmax‐Cmin)/Caverage}. Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady‐state plasma concentration‐versus‐time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 μg/mL.

Cefsulodin kinetics in renal impairment

Cefsulodin kinetics were determined after a 500‐mg dose to normal subjects and patients with varying degrees of renal insufficiency, including those requiring hemodialysis. Elimination kinetics were described by a two‐compartment model. Steady‐state volume of distribution was 0.26 l/kg regardless of renal function. When glomerular filtration rate (GFR) was more than 80 ml/min, elimination half‐life (t½) was 1.9 hr, total body clearance (ClT) was 2.01 ml/kg/min, and renal clearance (ClR) was 1.09 ml/kg /min. When GFR ranged from 79 to 53 ml/min, t½ was 2.9 hr, ClT was 1.17 ml/kg/min, and ClR was 0.65 ml/kg/min. In subjects with moderate renal failure in whom GFR was 32 to 22 ml/min, t½ was 5.7 hr, ClT was 0.66 ml/kg/min, and ClR was 0.26 ml/kg/min. In anuric patients t½ was 13.0 hr and ClT was 0.19 ml/kg/min or 9.5% of ClT in normal subjects. There was a linear relationship between ClT and GFR such that ClT = 0.19 + 0.017 GFR (r = 0.95). During hemodialysis the average plasma flow was 122 ml/min, dialyzer plasma clearance was 50.9 mllmin, plasma drug concentration was reduced by 60%, and t½ fell to 2.1 hr. After dialysis the elimination rate appeared to return to that in nondialysis studies. Therefore, renal failure reduces the ClT of cefsulodin. In hemodialysis patients the maintenance dose of cefsulodin should be reduced to 10% of normal and 60% of the dose should be given after hemodialysis.