An Approach to Predict the Ductus-Arteriosus Dilating Effect Induced by Lipo-Prostaglandin E1 in Newborn Rats Lacking Plasma Concentration-Time Data by the Pharmacological Response Kinetic Model.

Abstract

selectively dilate ductus arteriosus in many mammal neonates.1) A cyclodextrin preparation of PGE 1 (PGE 1 -CD)2) and a lipid microsphere preparation of PGE 1 (lipo-PGE 1 ) 3,4) have both been widely used in emergency treatment in neonatal patients with ductus dependent congenital heart diseases (D-CHDs). However, a fatal adverse drug reaction, apnea, may occur when PGE 1 is overdosed.5) Lipo-PGE 1 is a passive targeting-type drug delivery system (DDS) of PGE 1 , in which PGE 1 is dissolved in the lipid emulsion of soybean oil. 6) Momma retorted that the ductus-dilating intensity of lipo-PGE 1 was approximately ten times higher than that of PGE 1 -CD by the clinical monitoring of arterial blood pO 2 in D-CHD patients.3) Thus, lipo-PGE 1 therapy allows for a reduction of the total dose of PGE 1 . Further, the ductus-dilating effect after the discontinuation of lipo-PGE 1 administration lasts much longer than that of PGE 1 -CD. 4,7,8) However, its kinetics have not been clarified from the biopharmaceutical viewpoint. This makes it difficult to present evidence-based precise lipo-PGE 1 therapy in D-CHD patients.Pharmacokinetic analysis based on blood or plasma concentration profiles of drugs has been utilized for optimization of the dosage regimen. Pharmacokinetic/pharmacodynamic (PK/PD) modeling, which is an integrated mathematics model of a pharmacokinetic (concentration-time) and a pharmacodynamic (effect-concentration) event, is a useful tool for predicting the time course of pharmacological response. 9)Ordinary PK/PD modeling studies require validation of both the pharmacokinetic and pharmacodynamic aspects.10) However, it is difficult to obtain both the pharmacokinetic and pharmacodynamic data in, for example, the following cases: as a highly potent drug is administered in quite a low dose, it is difficult to determine plasma concentration of the drug; blood or plasma concentration has no mean in the targetingtype DDS drugs because systemic drug level does not reflect its local pharmacological response. The ductus-dilating effect of PGE 1 has been reported to be extremely potent.1) The clinical dose of lipo-PGE 1 (5 ng/kg/min), a targeting-type DDS, is too low to determine the plasma concentration profiles during the treatment. Thus, in the case of lipo-PGE 1 therapy in D-CHD patients, the acquisition of systemic pharmacokinetic data is technically impossible, and the pharmacokinetic analysis itself is meaningless. In such a case, validation of the model by systemic pharmacokinetic data is impossible, and the only way we can validate the model will be validation by the pharmacological response-time data.In this study, we have assessed changes in the diameter of ductus arteriosus after the bolus i.v. administration of lipo-PGE 1 in a multi-dose study to define a suitable pharmacological response kinetic model (PRK model) and related kinetic parameters. Also, we have investigated whether the model could predict the time course of the ductus-dilating effect under the constant infusion of lipo-PGE 1 . The utility...

Interventional effect of off-label use of alprostadil lipid microsphere injection in neurosurgical patients: a before-after study

“…When superabundant hydrosoluble solvents are added, demulsification is easy to be caused, which would decrease the targeting effect of the preparation and reduce the therapeutic efficacy. Moreover, demulsification may cause the leakage of prostaglandin E 1 , which is an inflammatory factor and heat source, and then cause adverse reactions such as phlebitis [24]. We found that before intervention Lipo-PGE 1 was always diluted by inappropriate menstruum such as invert sugar injection, multiple electrolytes and invert sugar injection, which are expensive and include fructose.…”

Intervention Efficacy of Off-Label use of Alprostadil Lipid Microsphere Injection on Neurosurgical Patients: A Retrospective Before-after Study

“…When superabundant hydrosoluble solvents are added to this formulation, the demulsi cation is easy to be caused, which would decrease its targeting effect and therapeutic e cacy. Moreover, demulsi cation may lead to the leakage of prostaglandin E1, an in ammatory factor and heat source, which stimulates blood vessels to produce serotonin and bradykinin, thus increasing capillary permeability and causing adverse reactions, such as phlebitis 29,30 . In our study, we found that Lipo-PGE 1 was always diluted by large amount of inappropriately solvents (0.02 or 0.04 or 0.1 µg/mL), such as invert sugar injection, multiple electrolytes and invert sugar injection, which include fructose, un-suitable for patients with hyperuricemia and gout, and were expensive.…”

Efficacy of administrative intervention for neurosurgical patients with off-label use of alprostadil lipid microsphere

“…When superabundant hydrosoluble solvents are added to this formulation, the demulsification is easy to be caused, which would decrease its targeting effect and therapeutic efficacy. Moreover, demulsification may lead to the leakage of prostaglandin E1, an inflammatory factor and heat source, which stimulates blood vessels to produce serotonin and bradykinin, thus increasing capillary permeability and causing adverse reactions, such as phlebitis 31 , 32 . In our study, we found that Lipo-PGE 1 was always diluted by large amounts of inappropriate solvents (0.02 or 0.04 or 0.1 μg/mL), such as invert sugar injection, multiple electrolytes, and invert sugar injection, which include fructose, unsuitable for patients with hyperuricemia and gout, and were expensive.…”