Gerald R. Rhodes

Pharmacokinetic/Pharmacodynamic Modeling in Drug Research and Development

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration‐time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so‐called integrated PK/PD‐models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD‐modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD‐modeling from an academic, industrial and regulatory perspective.

Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro

ABSTRACT Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; −15% to +37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 μM (lopinavir) to >100 μM (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.

Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis

To characterize the population pharmacokinetic of riluzole in patients with amyotrophic lateral sclerosis (ALS).

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in‐vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone‐releasing peptide SK&F 110679 and two GPIIb/ IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure‐transport studies are reviewed for this transporter. The tools for studying oral drug absorption in‐vivo involve animals bearing in‐dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided.

Absolute oral versus inhaled bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids.

Orally inhaled drugs provide great benefit in the treatment of asthma as they are delivered directly to the site of action, i.e. the lung. The absolute oral inhaled bioavailability of a glucocorticoid results from the combination of the bioavailability of the dose delivered to the lung and the bioavailability of the dose delivered into the gastrointestinal (GI) tract. The majority of the dose delivered to the lung is absorbed and available systemically. For the portion of the glucocorticoid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass/pre‐systemic metabolism in the GI tissue and liver. Since this oral component of the delivered dose does not provide any beneficial therapeutic effect but can contribute to the systemic side effects, it is desirable for the absolute oral bioavailability of inhaled glucocorticoids to be relatively low (which is the case with most of the glucocorticoids, < 25%). Another approach to limiting systemic exposure from inhaled delivery is to improve the effectiveness of the oral inhaled formulation and delivery device, by increasing the fraction of the total inhaled dose which reaches the lung. Since current inhalation technology can provide respirable fractions in the range of 30–50%, what is the significance of the oral component of systemic exposure in relation to the overall systemic exposure following the oral inhalation administration of glucocorticoids? Below a certain point (<25%), lower oral bioavailability of inhaled drugs may not be clinically important with respect to systemic exposure if the lung targeting is good (30%).

In vivo determination of drug kinetic linearity and individual organ elimination by the accelerated infusion technique

The objectives of this study were to (1) establish a controlled drug input method, accelerated infusion, for pharmacokinetic analysis in animals and (2) use the accelerated infusion method to determine the biological barriers responsible for the low oral bioavailability of a peptidic compound in rats. The method involves the administration of an infusion at flow rates which increase linearly with time, that is, accelerated infusion (AI). The accuracy of the system in delivering AIs was tested by comparing the observed volumes with the expected volumes. For experiments with the peptidic compound, a solution was administered by AI into the systemic circulation of rats via the carotid artery (IA). The pharmacokinetic linearity of the compound was determined from the linear phase of the concentration-time curve with the systemic clearance (CLs) calculated from the slope of the linear phase. Solutions of the peptidic compound were administered into the portal vein (IPV) or the inferior vena cava (IVC) by AI to assess the hepatic and pulmonary contribution to elimination. AIs into the duodenum (ID) assessed the roles of permeability and metabolism on the absorption of the peptidic compound across the intestinal mucosa. The system was reliable in delivering the desired AI in vitro. The pharmacokinetics of the peptidic compound in rats was linear up to 17 micrograms/ml in blood. Systemic clearance (CLs) of total compound in blood was calculated to be 31 ml/min/kg. Above 17 micrograms/ml, drug concentrations showed an upward deviation from linearity, indicating loss of linearity due to saturation of elimination. Plasma concentration-time profiles for IPV, IVC, and IA infusions were not substantially different. Our conclusions can be summarized as follows: (1) Accelerated infusion is a valuable, reliable approach that can be used to assess pharmacokinetics linearity, first-pass metabolism, and bioavailability. (2) The peptidic compound has a broad, linear kinetic range in rats, and nonlinearity at high concentration is due to saturation of elimination. (3) The compound has low first-pass elimination in the intestinal mucosa, liver, and lung. (4) The factor that determines the oral bioavailability in rats of the peptidic compound used in this study is mucosal permeability.

In vitro and in vivo techniques used in drug development for evaluation of dose delivery of inhaled corticosteroids.

Oral inhaled corticosteroids are important in the treatment of asthma since their delivery is targeted directly to the lung, which is the site of action. Triamcinolone acetonide (TAA) is an effective and safe corticosteroid that is marketed as a metered‐dose inhaler (MDI) with an integrated spacer (Azmacort®) for the treatment of asthma. Due to the phasing out of chlorofluorocarbon (CFC) propellants, Azmacort® has been reformulated with a non‐CFC propellant. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation of oral inhaled MDIs requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies to ensure clinical comparability for both efficacy and safety. This paper describes a chronological series of studies designed to support the reformulation of Azmacort®. These included in vitro studies to estimate respirable fraction, in vivo pulmonary deposition studies, in vivo pharmacokinetic‐pharmacodynamic studies to estimate the systemic effects of each formulation, and final clinical studies in adult and pediatric patients to confirm the clinical comparability of the new formulation of Azmacort®. The results of these studies, performed at various stages during the development of new formulations, were critical in guiding the reformulation efforts for Azmacort®.

Application of Clinical Trial Simulation in Exploring The Safety Profile of Docetaxel (D) in Cancer Patients

Clinical Pharmacology & Therapeutics (1999) 65, 198–198; doi: