Value of PKPD

In drug development, the ADME processes of a compound are experimentally determined (Figs. 6.2 and 6.3). Absorption studies are conducted to answer the basic question whether the drug can reach the systemic circulation from the site of administration. There are several factors that can influence the absorption of the drug after oral administration. The drug needs to have a high solubility and high permeability in order to be absorbed adequately. A Biopharmaceutics Classification System (BCS) was proposed to classify drug molecules into one of four classes based on their solubility and permeability through the intestinal cell layer. The combination of BCS and in vitro-in vivo correlation (IVIVC) improves the efficiency of the drug development and review process—a class of immediate release (IR) solid oral dosage forms for which bioequivalence (BE) may be assessed based solely on in vitro dissolution results (biowaiver). In vitro transport studies can be conducted to evaluate the involvement of efflux pumps (P-glycoprotein) or certain molecules that serve as ligands for membrane pumps (OATP, OAT, etc.) to transport drugs across the gastrointestinal tract. Except transporters, first-pass effects including intestinal and liver metabolism and certain forms of bile excretion can affect the amount of drug eventually reaching the blood circulation. In addition, food can also affect the drug absorption. Required by the regulatory agencies, food-effect studies become standard PK trials in the industrial development of orally administered drugs.

Using radiolabelled material, quantitative whole-body autoradiography (QWBA) provides a rapid, cost-effective, and accurate assessment of the tissue distribution of radioactivity.

Types of experiments

Physiological relevance o In-vitro

Metabolism > Metabolic stability J> CYP enzyme inhibition / induction

> Metabolite identification C In-vivo

14C mass balance

> Drug drug interaction

^ Active or toxic metabolites

> Potential of inhibiting / inducing effect on metabolism of other drugs

> Potential of exposure changes under inhibitors / inducers

O 14C mass balance for fecal / ^ Sustainable

Eliminati0n urine / exp'red air excreta concentration / effect

C Comparing calculated > Predicting effect of lM to liver blood flow __ disease status or physiological factors on PK

CLm to liver blood flow or calculated CLR to GFR C Special populations

Fig. 6.3. Absorption, Distribution, Metabolism, & Elimination (ADME) -2

The study demonstrates if drug-related material reaches a target organ (e.g., CNS) and identifies sites of accumulation or unusual persistence. The measurement of protein binding is also important as it is postulated that only the unbound component of the drug is pharmacologically active and can be removed from the body. In in vivo studies, the apparent volume of distribution determined for a compound is a direct measure of extent of distribution, and it should be compared against the physiological volumes of plasma, extracellular space, and total body water in the corresponding species.

Metabolism studies (Fig. 6.3) identify the potential metabolites that may be active or even toxic, identify enzymes involved in the metabolism of new chemical entities (NCEs), determine the rates of these enzyme reactions, and demonstrate the inhibition or induction potential of NCEs on the enzymes. The importance of drug metabolism is twofold: (a) drugs can be extensively metabolized by a specific enzyme or by several enzymes; (b) drugs can also affect the activities of the enzymes by either decreasing their intrinsic activity (inhibition) or increasing the amount of available enzyme (induction). The consequences of the drug metabolism can lead to significant drug-drug interactions resulting in either loss of efficacy or toxicity. Sometimes, the rate and extent of drug metabolism is directly related to the efficacy of the drug, such as in the case of prodrug or pharmacologically active metabolites (e.g., terfe-nadine to fexofenadine, loratadine to desloratadine, leflunomide to teriflunomide). In some cases, the absence of certain drug metabolizing enzymes or significantly reduced capacity in certain subjects can have profound effects on elimination of drugs that are primarily metabolized by the enzymes leading to toxicity. In other cases, biotransformation of drugs can also lead to formation of reactive intermediates or metabolites that interact with endogenous macromolecules, such as proteins and nucleic acids. It is, therefore, important not only to study the parent compound but also to study the active/toxic metabolites during drug development.

Drugs are primarily eliminated by the feces or via the urine, and this can be determined by mass balance studies. The other routes of elimination such as via the lungs or biliary excretion can also be determined. The drug's clearance (CL) in PK studies can be compared with blood flows through the liver and kidney and glomerular filtration rate (GFR). Function of the excretory organs, especially the kidney, can have dramatic impact on organ physiology and a drug's elimination and its half-life, leading to persistent effects and lower dose needs or toxicity. PK work in this situation may be important element of product development for patient safety. Predicating elimination of a drug based on various excretory studies is a key part of MPK's contribution to product development, product dosing, and safety.

"Exposure" to a drug as defined by either plasma concentration or a surrogate of concentration, such as AUC (area under the concentration-time curve) or Cmax (maximum drug concentration), can be correlated to a pharmacodynamic response (Fig. 6.4), either efficacy or safety data, using the following PK/PD models according to the data types (continuous or categorical), the time course of response relative to concentration, and the shape of the curve when plotting response against concentration.

• Linear or log linear: The model assumes that the effect will continuously increase with increasing concentrations.

• E or sigmoidal E . The model describes the interaction max ° max between small molecules such as drugs and large molecules such as receptors or enzymes including the shape of the response, the baseline effect, or the maximal possible effect.

• Indirect link or indirect response: Indirect link uses a hypothetical effect compartment model to accommodate the drug distribution to the biophase. Indirect response model is used if the rate-limiting step is a postreceptor event. For indirect link models, time for maximal effect (T ) is independent of dose whereas for indirect response models, T

max,e increases with increasing dose.

• Logistic: These models can correlate frequency of a categorical response to the drug concentration or dose.

It is important that there is sufficient characterization of the following parameters:

• Baseline effect: A physiological parameter is evaluated and quantified without drug dosing. Baseline can change due to circadian rhythm (e.g., circadian rhythm of cortisol or mela-tonin levels), food, or disease.

• Biomarker: It is a quantifiable physiological or biochemical marker that is sensitive to intervention (drug treatment). Biomarker might or might not be relevant for monitoring clinical outcome, usually used in early drug development. Validation of its relevance to disease outcomes is needed.

• Surrogate marker: If a biomarker has been shown to reflect clinical outcome, it can be called surrogate marker; for example, HIV load in AIDS patients, blood sugar in diabetes patients, FEV1 in asthma patients, and urine NTx or

Pharmacokinetics (PK) Pharmacodynamics (PD)

Pharmacokinetics (PK) Pharmacodynamics (PD)

Fig. 6.4. Pharmacokinetic/Pharmacodynamic

Bioavailability (F) = Absorption - Metabolism - Efflux - Degradation

Bioavailability (F) = Absorption - Metabolism - Efflux - Degradation

Fig. 6.5. Bioavailability and Bioequivalence

Source: Adapted from Rowland M and Tower N, Clinical Pharmacokinetics 3rd Ed., 1995. Lippincott Williams and Wilkins.

Fig. 6.5. Bioavailability and Bioequivalence

Source: Adapted from Rowland M and Tower N, Clinical Pharmacokinetics 3rd Ed., 1995. Lippincott Williams and Wilkins.

CTx (N- or C- telopeptide cross-links), and bone mineral density for osteoporosis. • Clinical end point: A characteristic or variable that measures how a patient feels, functions, or survives and directly relates to disease outcome. However, assessment is often difficult to perform requiring a large number of patients and/or longer time frame for significant change and/or consensus of its relevance to meaningful disease change [1].

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