Andreas Svennebring

Net present value approaches for drug discovery.

Three dedicated approaches to the calculation of the risk-adjusted net present value (rNPV) in drug discovery projects under different assumptions are suggested. The probability of finding a candidate drug suitable for clinical development and the time to the initiation of the clinical development is assumed to be flexible in contrast to the previously used models. The rNPV of the post-discovery cash flows is calculated as the probability weighted average of the rNPV at each potential time of initiation of clinical development. Practical considerations how to set probability rates, in particular during the initiation and termination of a project is discussed.

Visualization of Plasma and Tissue Binding Using Dose Fractions Parameter

A novel concept of dose fractions, based on the distribution of total bioavailable dose between the six combinations of location and binding state in Øie–Tozers model is suggested as a way to visualize the distribution pharmacokinetics of a drug. The concept of dose fractions provides a sharper terminology in discussions of drug distribution allowing for a more precise description of the state and location of a drug within a system. In medicinal chemistry literature, the free fraction of a drug in plasma is a commonly discussed factor affecting the exposure to free drug while tissue binding is less well addressed. The free dose fraction, defined as the fraction of the bioavailable dose existing in free form, is suggested as a potentially valuable term for such discussions. Presently, drugs with high (>95%) plasma protein binding are viewed with skepticism, the rational behind which is questioned. The plasma protein bound dose fraction defined as the fraction of the total available dose, which is bound to plasma proteins, is suggested as a measure of the risk for problems related to fluctuations in free drug exposure due to variations in the concentration of drug binding plasma protein.

Investigation of the prerequisites for the optimization of specific plasma protein binding as a strategy for the reduction of first-pass hepatic metabolism

Abstract 1. It is hypothesized that the deliberate structural tailoring of compounds designed for drug use to increase the specific plasma protein binding can be used to reduce first-pass hepatic metabolism. To test the feasibility of this hypothesis, a dataset of drugs with plasma protein binding of 90% or above divided into three classes including 50 acids, 44 bases and 69 neutrals was analyzed. 2. Among the drugs with ≥99% plasma protein binding, the fraction of the total dose existing in free form in vivo (free dose fraction) decreased in the following order: acids (0.55%) > neutrals (0.16%) > bases (0.08%). The order was different for the fraction of the total dose that existed in plasma protein bound form (plasma protein bound dose fraction): acids (58%) > neutrals (17%) = bases (18%). 3. The free fraction was poorly correlated with the partition coefficient (Log P). The lower aqueous solubility associated with high plasma protein binding was explained by differences in Log P and not by the plasma protein binding per se. The logarithm of the extrarenal clearance was correlated with Log P. For acids and bases, extrarenal clearance was also correlated with fu. For neutrals, plasma protein binding had no protective effect.

The impact of the concentration of drug binding plasma proteins on drug distribution according to Øie-Tozer’s model

Abstract 1. New equations have been developed from an updated version of Øie-Tozer’s model expressing how the free concentration and volume of distribution change in relation to changes in the concentration of drug binding plasma proteins. This updated model accommodates more than one drug binding plasma protein to contribute to the plasma protein binding. 2. Demonstrations of the model show that variability in the concentration of one plasma protein has considerably less impact on the free drug concentration and volume of distribution if other plasma proteins contribute to binding, than if they don’t.

The role of intramolecular self-destruction of reactive metabolic intermediates in determining toxicity

When reactive centers are formed in chemical conversions, intermolecular reactions tend to dominate over intramolecular alternatives whenever both alternatives are possible. Hence, when reactive metabolites are formed from xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may play an important role in reducing toxicity related to reactive intermediates. The phenomenon is likely to be particularly noticeable for toxicophores that are readily associated with a type of toxicity that is rarely caused by other structural motives. In two demonstrative investigations, it is concluded that nitrobenzenes for which the expected nitrosyl metabolite is likely to react with adjacent groups are less toxic than what is rationally expected, and that among aryl amine drugs allowing for the immediate quenching of the corresponding N‐aryl hydroxylamine metabolite, the typical erythrocyte toxicity often seen with aryl amines is absent. The deliberate introduction of effective quenching groups nearby a toxicophoric moiety may present a potential strategy for reducing toxicity in the design of drugs and other man‐made xenobiotics. Copyright

The usefulness of Øie–Tozer’s model in deriving pharmacokinetic changes in response to changes in the concentration of drug-binding plasma protein

Abstract 1. Øie–Tozer’s model can be used to derive changes in the distribution of drugs in relation to changes in the concentration of drug binding plasma proteins. 2. Concerns have been raised that the model is invalid for this purpose because it does not account for active drug transport, pH differences between fluids and extracellular tissue binding. 3. Here, it is demonstrated that these imperfections do not affect the outcome of the calculation.

The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value

Preclinical Research