Challenges, approaches and enablers: effectively triangulating towards dose selection in pediatric rare diseases.

Dose selection is an integral part of a molecule's journey to become medicine. On top of typical challenges faced in dose selection for more common diseases, pediatric rare disease has additional unique challenges due to the combination of 'rare' and 'pediatric' populations. Using the central theme of maximizing 'relevant' information to overcome information paucity, dose selection strategy in pediatric rare diseases is discussed using a triangulation concept involving challenges, approaches and very importantly, enablers.

International consortium for innovation and quality: An industry perspective on the nonclinical and early clinical development of intravitreal drugs.

The eye, which is under constant exposure to environmental pathogens, has evolved various anatomic and immunological barriers critical to the protection of tissues lacking regenerative capacity, and the maintenance of a clear optic pathway essential to vision. By bypassing the ocular barriers, intravitreal (IVT) injection has become the mainstay for the delivery of drugs to treat conditions that affect the back of the eye. Both small molecules and biotherapeutics have been successfully administered intravitreally, and several drugs have been approved for the treatment of (wet) age-related macular degeneration and diabetic macular edema.

Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment.

Aim: This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function.

Methods: Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors.

Background: Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment.

Methods: Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.

Impact of Dose Reduction on Efficacy: Implications of Exposure-Response Analysis of Palbociclib.

Background: Palbociclib is indicated for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC).

Objective: Exposure-response analyses were conducted to evaluate efficacy in Asian versus non-Asian patients and in patients with versus without dose reduction in PALOMA-2.

Patients And Methods: PALOMA-2 compared palbociclib plus letrozole versus placebo plus letrozole in patients with ABC.

Population Pharmacokinetics of Talazoparib in Patients With Advanced Cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patients with advanced cancers using pooled data from these 4 studies.

Distribution, Metabolism, and Excretion of Gedatolisib in Healthy Male Volunteers After a Single Intravenous Infusion.

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion.

Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib.

Ocular Pharmacokinetics.

Although the fundamental concepts of pharmacokinetics remain the same, ocular pharmacokinetics has its own challenges due to the uniqueness of barrier properties posed by various ocular tissues and its growing complexity with different routes of ocular administration. A thorough understanding of the barrier nature will aid in tailoring a drug or its carrier's physicochemical properties to its advantage. In order to deliver the right payload of a drug at the target site, various approaches can be taken to leverage the pharmacokinetics that includes molecular design based on desirable physicochemical properties, formulation approaches, and alternative routes of administration.

Optimal sampling scheme for estimation of intraocular pressure diurnal curves in glaucoma trials.

Background And Objective: Effective control of intraocular pressure (IOP) is essential for the successful management of glaucoma. IOP exhibits diurnal variation, yet continuous monitoring is impractical. To date, no clear evidence exists on the number of sampling timepoints required to characterize diurnal IOP and when those measurements should be collected.

Mechanism - based translational pharmacokinetic - pharmacodynamic model to predict intraocular pressure lowering effect of drugs in patients with glaucoma or ocular hypertension.

Purpose: To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT).

Methods: Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature.

Intraocular distribution of melanin in human, monkey, rabbit, minipig and dog eyes.

The purpose of this study was to quantify the melanin pigment content in sclera, choroid-RPE, and retina, three tissues encountered during transscleral drug delivery to the vitreous, in human, rabbit, monkey, minipig, and dog models. Strain differences were assessed in NZW × NZR F1 and Dutch belted rabbits and Yucatan and Gottingen minipigs. The choroid-RPE and retina tissues were divided into central (posterior pole area) and peripheral (away from posterior pole) regions while the sclera was analyzed without such division.

Comparison of long-acting bevacizumab formulations in the treatment of choroidal neovascularization in a rat model.

Objective: The objective of this study was to compare the reduction in size of experimentally induced choroidal neovascularization (CNV) in rat eyes treated with bevacizumab, poly(ethylene-glycol) (PEG)-bevacizumab conjugate (b-PEG), and poly(lactic-co-glycolic acid) (PLGA)-encapsulated bevacizumab (b-PLGA).

Methods: Forty-eight eyes from 24 rats were divided into 4 groups of 12 eyes. In each group, 3 eyes were assigned to a treatment subgroup, each receiving a different injection-control, bevacizumab, b-PEG, and b-PLGA.

Nanosized dendritic polyguanidilyated translocators for enhanced solubility, permeability, and delivery of gatifloxacin.

Purpose: Dendrimeric polyguanidilyated translocators (DPTs) are nanosized novel dendrimers that efficiently translocate molecules across biological barriers. The purpose of this study was to develop a DPT that could serve as an ophthalmic delivery vehicle for gatifloxacin and to evaluate its in vitro and in vivo delivery after topical application.

Methods: The gatifloxacin (GFX) solubility-enhancing property of a six-guanidine group-containing dendrimer (g6 DPT) was investigated as a function of pH and dendrimer concentration.

Targeted drug and gene delivery systems for lung cancer therapy.

Purpose: To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone-releasing hormone (LHRH) agonist, and its combination in vivo with RGD peptide conjugated nanoparticles encapsulating an antiangiogenic, anti-vascular endothelial growth factor (VEGF) intraceptor (Flt23k; RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice.

Experimental Design: The in vitro and in vivo efficacy of the deslorelin-docetaxel conjugate was evaluated in H1299 cells and xenografts in athymic nude mice. Coadministration of deslorelin-docetaxel conjugate and RGD-Flt23k-NP was tested in vivo in mice.

Subconjunctival nanoparticle carboplatin in the treatment of murine retinoblastoma.

Objective: To evaluate the efficacy of subconjunctival nanoparticle carboplatin in the treatment of transgenic murine retinoblastoma.

Methods: Dendrimeric nanoparticles loaded with carboplatin were prepared. Forty LHbeta-Tag mice were randomly assigned into 4 groups and treated at 10 weeks of age.

Influence of dosage form on the intravitreal pharmacokinetics of diclofenac.

Purpose: To prepare a suspension form of diclofenac and compare the influence of the injected form (suspension versus solution) on the intravitreal pharmacokinetics of diclofenac in Dutch belted pigmented rabbits.

Methods: Diclofenac acid was prepared and characterized in a suspension formulation. Rabbit eyes were injected with either diclofenac sodium solution (0.

Luteinizing hormone-releasing hormone receptor-targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy.

Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel.

Human scleral diffusion of anticancer drugs from solution and nanoparticle formulation.

Purpose: To determine the transscleral permeability of chemotherapeutic drugs vinblastine and doxorubicin for treatment of intraocular tumors, and to compare the use of doxorubicin encapsulated in PLGA and liposome nanoparticles.

Methods: Human sclera was isolated and mounted in a Lucite chamber. Fluorescently tagged vinblastine (VIN), innately fluorescent free doxorubicin (DOX), PLGA doxorubicin (PLGA-DOX), or Doxil (Tibotec Therapeutics) were added to the episcleral donor chamber.

Prediction of vitreal half-life based on drug physicochemical properties: quantitative structure-pharmacokinetic relationships (QSPKR).

Purpose: The aim of this study was to develop quantitative structure pharmacokinetic relationships (QSPKR) to correlate drug physicochemical properties (molecular weight, lipophilicity, and drug solubility), dose, salt form factor, and eye pigmentation factor to intravitreal half-life in the rabbit model.

Methods: Dataset derived from prior literature reports, which included molecules with complete structural diversity, was used to develop the QSPKR models. Entire dataset as well as subsets limited to albino rabbit data, pigmented rabbit data, acids, bases, zwitterions, neutral compounds, suspensions, and macromolecules were analyzed.

Novel approach for delivery of insulin loaded poly(lactide-co-glycolide) nanoparticles using a combination of stabilizers.

Insulin stability during microencapsulation and subsequent release is essential for retaining its biological activity. The successful delivery of insulin relies on the proper selection of stabilizers in addition to other parameters. Attempts were made to address the problem with a few combination of stabilizers for maintaining the integrity of insulin during formulation and delivery.

Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.

Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats.

Development and validation of a reversed-phase HPLC method for determination of nitrendipine in rat plasma: application to pharmacokinetic studies.

A simple and sensitive method for the determination of nitrendipine in rat plasma was developed using high-performance liquid chromatography (HPLC). The procedure involves extraction of nitrendipine in dichloromethane/sodium hydroxide, followed by reversed phase HPLC using a Waters, Spherisorb ODS2 (250 x 4.6 mm, 5 microm) column and UV detection at 238 nm.

Development and evaluation of nitrendipine loaded solid lipid nanoparticles: influence of wax and glyceride lipids on plasma pharmacokinetics.

Nitrendipine is an antihypertensive drug with poor oral bioavailability ranging from 10 to 20% due to the first pass metabolism. For improving the oral bioavailability of nitrendipine, nitrendipine loaded solid lipid nanoparticles have been developed using triglyceride (tripalmitin), monoglyceride (glyceryl monostearate) and wax (cetyl palmitate). Poloxamer 188 was used as surfactant.

The development of folate-PAMAM dendrimer conjugates for targeted delivery of anti-arthritic drugs and their pharmacokinetics and biodistribution in arthritic rats.

The aim of this study was to synthesize folate-dendrimer conjugates as suitable vehicle for site specific delivery of anti-arthritic drug (indomethacin) to inflammatory regions and to determine its targeting efficiency, biodistribution in adjuvant induced arthritic rats. Folic acid was coupled to the surface amino groups of G4-PAMAM dendrimer (G4D) via a carbodiimide reaction and loaded with indomethacin. The conjugates were characterized by (1)H-NMR and IR spectroscopy.