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Abstract

A physiologically based model is presented to aid prediction of the pharmacological benefits to be derived from the administration of a drug as a targeted drug-carrier combination. An improvement in the therapeutic index and an increase in the therapeutic availability are the primary benefits sought. A measure of the former is obtained from the value of the drug targeting index, a newly derived parameter. Both the drug targeting index and the therapeutic availability are directly calculable. The minimum information needed for approximating both parameters is the candidate drug's total-body clearance and some knowledge of the target site's anatomy and blood flow. Drugs with high total-body clearance values that are known to act at target tissues having effective blood flows that are small relative to the blood flow to the normal eliminating organs will benefit most from combination with an efficient, targeted carrier. Direct elimination of the drug at the target site or at the tissue where toxicity originates dramatically improves the drug targeting index value. The fraction of drug actually released from the carrier at both target and nontarget sites can radically affect index values. In some cases a 1% change in the fraction of the dose delivered to the target can result in a 50% change in the drug targeting index value. It is argued that most drugs already developed have a low potential to benefit from combination with a drug carrier. The approach allows one to distinguish clearly those drugs that can benefit from combination with targeted in vivo drug carriers from those drugs that cannot.

Reformulating Tylocrebrine in Epidermal Growth Factor Receptor Targeted Polymeric Nanoparticles Improves Its Therapeutic Index

“…Thus, the advantage gained by nanoencapsulation strongly depends on the drug being investigated. 19 , 43 Additionally, A431 tumors were found to be fluid-filled (not shown), suggesting that the interstitial fluid pressure in these tumors is high, as previously reported. 44 , 45 High interstitial fluid pressure (IFP) is likely to affect the intratumoral transport of nanoparticles more significantly than that of free drug molecules.…”

“…The relative benefit of using the nanoparticulate formulation over the free drug was determined using the drug targeting index (DTI). 19 The DTI was calculated as shown below: …”

Microscopy and tunable resistive pulse sensing characterization of the swelling of pH-responsive, polymeric expansile nanoparticles

“…23, 26, 27 Several pH-responsive nanoparticle delivery systems have been developed. Among others, Murthy and collaborators have used pH-responsive polymeric particles to increase the uptake and endosomal release of oligonucleotides in hepatic cells.…”

“…21 Of these many triggers, pH-responsive materials are frequently selected for applications involving delivery to tumors or sites of inammation due to the lower pH prole ubiquitous in these tissues. 23,26,27 Several pH-responsive nanoparticle delivery systems have been developed. Among others, Murthy and collaborators have used pH-responsive polymeric particles to increase the uptake and endosomal release of oligonucleotides in hepatic cells.…”

Nonviral Approaches Satisfying Various Requirements for Effective in Vivo Gene Therapy.

“…Pharmacokinetic considerations clearly show that drug delivery to a target is always greater with the intraarterial route than the intravenous one. 42) Topical administration of drug into the skin, muscle, trachea, and oral cavity is sometimes used to obtain local or systemic effects, although it is difficult to retain the drug around the injection site because of its absorption into the systemic circulation.…”