Special Issue:
Challenges and Opportunities in Pharmacokinetics
Stephen Bevan Shrewsbury, MBChB
Impel Pharmaceuticals Inc., Seattle, WA, USA
Greg Davies, BSc (Hons)
Impel Pharmaceuticals Inc, Seattle, WA, USA
Lisa McConnachie, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA
John Hoekman, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA
Abstract
Nasal drug delivery presents a potential opportunity for achieving rapid, extensive drug absorption via a nonoral route by 1) avoiding degradation within the gastrointestinal tract and first-pass metabolism in the liver and 2) facilitating faster onset via rapid absorption into the bloodstream. However, the site of drug deposition within the nasal cavity may impact drug pharmacokinetics. Precision Olfactory Delivery (POD®) by Impel Pharmaceuticals Inc. is a new technology that provides handheld, manually actuated, propellant-powered drug delivery to the upper nasal space for rapid and efficient absorption. Rapid onset of effect can be a major advantage in many clinical applications where quick and effective administration is needed (eg, alleviating agitation in emergency settings or reducing debilitating migraine symptoms). Here, we review the pharmacokinetic profile of INP105, which is being developed to deliver olanzapine (OLZ) by POD to treat agitation in patients with autism. Because formulation can play a large role in the pharmacokinetic profile of a nasally administered drug, we provide a comprehensive review of both published and previously unpublished preclinical data outlining how the INP105 formulation was developed and optimized for study in humans. Multiple formulation carriers and excipients were tested to find a stable INP105 formulation with a desirable nasal absorption profile. Because the nasal architecture in nonhuman primates (NHPs) is similar to humans, the pharmacokinetics and tolerability of an INP105 combination product (NHP-INP105) using a clinical formulation combined with a device specifically designed for NHPs has been investigated in preclinical NHP studies, providing translational data for human studies and the pathway for testing novel products and formulations. The pharmacokinetics and tolerability of INP105 were then evaluated in an early clinical study in humans, demonstrating favorable pharmacokinetic and pharmacodynamic profiles. In this review, we aim to illustrate how delivery of therapeutics to the upper nasal space using POD, such as with agents like INP105, has the potential to optimize nasal delivery and unlock the potential of delivery-limited drugs to provide patients with rapid onset of effect, ease of use, and convenience.
Jagadeesh S Rao
IGC Pharma LLC., Potomac, MD, USA.
William Julio
SCB Research, Bayamón, Puerto Rico, USA.
Varduhi Ghazaryan
IGC Pharma LLC., Potomac, MD, USA.
Evelyn Gutiérrez
IGC Pharma LLC., Potomac, MD, USA.
Claudia Grimaldi
IGC Pharma LLC., Potomac, MD, USA.
Saadia S Shahnawaz
IGC Pharma LLC., Potomac, MD, USA.
Laura Sánchez
IGC Pharma LLC., Potomac, MD, USA.
Maria Alejandra Tangarife
IGC Pharma LLC., Potomac, MD, USA.
María Juanita Arbeláez
IGC Pharma LLC., Potomac, MD, USA.
María Margarita Venegas
IGC Pharma LLC., Potomac, MD, USA.
Laura Delgado- Murillo
IGC Pharma LLC., Potomac, MD, USA.
Ram Mukunda
IGC Pharma LLC., Potomac, MD, USA.
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects over 55 million people worldwide. Individuals with AD are often prescribed multiple medications to manage comorbidities, many of which are metabolized by enzymes from the cytochrome P450 (CYP). CYP2C9 is expressed by the CYP2C9 gene. The highly polymorphic gene is grouped into phenotypes such as poor, intermediate, normal, and ultra-rapid metabolizers that influence the pharmacokinetics (PK) of drugs and their metabolites. Among humans, CYP2C9 is one of the most essential enzymes for metabolizing drugs, including delta-9-tetrahydrocannabinol (THC). The enzyme converts THC into its active metabolite 11-hydroxy-delta-9-THC (OH-THC). IGC-AD1 is a formulation with two active pharmaceutical ingredients, delta-9-THC and melatonin. The Phase 1, multiple ascending dose (MAD) trial, was conducted on a Puerto Rican population. The participant population in the trial (N=13) was 69.2% female and 30.8% male, with an average age of 80.18 (SD+/- 6.22). We report on the effect of CYP2C9 polymorphisms on the pharmacokinetics (PK) of THC and its active metabolite in AD patients from a Phase 1 trial. Using a Mass ARRAY Analyzer 4 Instrument (Invitae Inc.), we determined the following CYP2C9 alleles: *2, *3, *4, *5, *6, *8, *11, *13, *15, and found that 60% of participants (N=6) were carriers of at least one polymorphism including 1*/2* and 1*/3*. The participants with intermediate metabolizers (*1/*3 and *1/*2) showed an increased half-life of THC and OH-THC with major differences between the two intermediate metabolizer groups *1/*3 and *1/*2. In the trial more females were noted to be intermediate metabolizers than males. As polymorphisms of CYP2C9 affect the PK of THC and its metabolite, larger studies are needed to establish PK baselines for polymorphisms of CYP2C9. In the meantime, it is recommended that researchers exercise caution while dosing AD patients with THC.
David J. Tittle
ElleVet Sciences, Product Development and Scientific Communications, South Portland, ME 04106
Joseph J Wakshlag
Department of Clinical Sciences, Cornell College of Veterinary Medicine, Ithaca, NY 14853
Wayne S Schwark
Department of Molecular Medicine, Cornell College of Veterinary Medicine, Ithaca, NY, 14853
Alex Lyubimov
University of Illinois at Chicago, Department of Pharmacology, Chicago IL, 60612
Alexander Zakharov
University of Illinois at Chicago, Department of Pharmacology, Chicago IL, 60612
Beatriz Gomez
University of Illinois at Chicago, Department of Pharmacology, Chicago IL, 60612
Abstract
The aim of this study was to compare the pharmacokinetics of a cannabidiol (CBD) and cannabidiolic acid-rich (CBDA) hemp extract in a sesame oil base and a soft gel capsule formulation. During acute twenty-four hour pharmacokinetic evaluation, maximum serum concentration (Cmax) was higher for all measurable components in the serum (CBD, CBDA, Δ-9-tetrahydrocannabinol [THC] and tetrahydrocannabinolic acid [THCA]) following soft gel administration versus the oil formulation. Similar times of maximal serum concentration (Tmax) were observed with both presentations. Based on the area under the curve, a significant increase in CBDA absorption was observed following soft gel dosing. Whilst comparable, the steady state pharmacokinetic data after one week of twice daily dosing shows an increased concentration of CBDA, with a slightly lower CBD concentration with soft gel administration compared to oil. Although THC and THCA concentrations remain comparably low from both presentations, THCA absorption was superior regardless of formulation. When examining acceptance, soft gels are associated with increased palatability and less rejection of oral dosing with oil. Dogs, and potentially even people, may show increasing tolerance to this soft gel formulation; as such consideration should be given to the ease of administration and superior CBDA absorption with the use of a soft gel formulation of a CBD/CBDA hemp blend.
Abstract
Nanomedicine is a rapidly emerging interdisciplinary field in which medicine is coupled with nanotechnology tools and techniques for advanced therapy with the aid of molecular knowledge. Nanoscale drug delivery systems provide a platform to improve the pharmacokinetics and increase the bio-distribution of therapeutic agents to target organs, thereby resulting in improved efficacy while limiting drug toxicity. These systems have revolutionized drug delivery approaches and are exploited for therapeutic purposes to carry the drug in the body in a controlled manner from the site of administration to the therapeutic target. Several promising molecular targets that have been identified as potential therapies for acute and chronic respiratory conditions have been limited because of difficulty with delivery systems. In particular, delivery of peptides, proteins, miRNAs to the lung is an ongoing challenge. Hence, it is an attractive strategy to test potential targets by employing a nanotechnology approach. Nanobiotechnology and nanoscience can provide innovative techniques to deliver drugs targeted to the site of inflamed organs. Here we review some of the nanomedicine approaches that have been proposed and studied over the last decade to facilitate the delivery of therapeutic agents specifically for acute and chronic lung diseases. Development of nano-sized carriers including nanoparticles, or liposomes holds great potential for diagnosis and advanced delivery systems for immunomodulation in respiratory diseases; however translational studies are urgently needed to validate the use of nanotechnology for clinical applications.
Markus Roucka
VelaLabs GmbH
Klaus Zimmermann, Dr.
VelaLabs GmbH
Markus Fido, Dr.
VelaLabs GmbH
Abstract
Approximately 50 – 60% of all human proteins are glycosylated. Glycosylation can not only affect the structure of proteins, but also their biological activity, serum half-life, pharmacokinetics, pharmacodynamics, and immunogenicity. For biotechnologically derived proteins, analysis of glycosylation patterns is thus of utmost importance. Standard techniques are based on high performance liquid chromatography, mass spectrometry and capillary electrophoresis. Lectin microarrays are an orthogonal tool which is very promising for studying glycosylation patterns. However, though the advantages of lectin arrays for the analysis of glycoproteins have been discussed especially in review articles currently only a handful of publications are available, which are presenting data about therapeutic proteins analyzed with this promising technology. Within this review article, important aspects for analysis of therapeutic glycoproteins are highlighted from the perspective of the lectin array technology. This includes cell lines for the production of therapeutic proteins, influence of cell culture conditions on glycosylation, glycosylated antibodies and their effector functions, glycoengineering, regulatory guidance for biosimilars and methods for glycosylation analysis with special emphasis on lectin microarrays. The available literature proves that especially the lectin array technology is a upcoming tool for screening the glycosylation pattern of biotechnologically produced proteins. The technology is also versatile and more applications will be utilized in the near future for example for biomarker resarch and application as a diagnostic tool.
Vijay Kumar
Univ. of Colorado, Anschutz Medical Campus
Michael F Wempe
Univ. of Colorado, Anschutz Medical Campus
Janet W. Lightner
Department of Pharmacology, East Tennessee State University Johnson City, TN 37614, USA
Peter J. Rice
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, East Tennessee State University Johnson City, TN 37614, USA
Marielle Nebout
INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France.
Jean-Francois Peyron
c INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France.
Abstract
Histone methyl-transferase Dot1L can methylate histone 3 on lysine 79 (H3K79). Herein we present the chemical synthesis of a cis/trans mixture of a potent Dot1L inhibitor known as EPZ-5676 (2). Upon preparing compound 2, we tested the compound in mixed and non-mixed lineage leukemia cell lines. The two MLL-rearranged cell lines were MV4;11 and Molm14; whereas the two non-MLL-rearranged (control) cell lines were Molt4 and Kasumi. We observed anticipated in vitro activity for compound 2 in these four leukemia cell lines; results illustrating that Dot1L inhibition can trigger cancer cell death. In addition, we also tested 2 in a new leukemia cell line known as KO99L; KO99L cells have been shown to over express the membrane amino acid transporter known as L-amino acid type 1 (LAT1). Compound 2 was also observed to decrease cell viability in the KO99L cell; albeit at higher concentrations as compared to the MLL-rearranged cell lines. In addition to in vitro experiments, we also performed in vivo experiments in Sprague-Dawley rats. Intravenous (i.e. orbital sinus dosing) experiments were performed at two different doses (i.e. 1.0 and 2.0 mg/kg). These rat Pharmacokinetic (PK) results indicate that compound 2 has a slow distribution phase, followed by an extended terminal half-life (i.e. 11.2 ± 3.1 h). Furthermore, tissue distribution experiments demonstrate that 2 predominately distributes to kidney, blood and liver, and to a limited extend, was detectable in brain.
Alan D. Kaye, MD, PhD
Provost & Vice Chancellor of Academic Affairs, Department of Anesthesiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport LA 71103
George M. Jeha
Medical Student, LSU School of Medicine, New Orleans, and Research Associate, Department of Anesthesiology, LSU Health Sciences Center, Room 656, 1542 Tulane Ave., New Orleans, LA 70112
Jordan Renschler, BS
Medical Student, LSU Health Sciences Center New Orleans, 1901 Perdido Street, New Orleans, LA 70112
Mitchell C. Fuller, BS, (MD, anticipated)
Medical College of Wisconsin, 8701 W Watertown Plank Rd, Wauwatosa, WI 53226
Alex D. Pham, MD
Anesthesiology Resident, PGY – 1, Department of Anesthesiology LSU Health New Orleans, 1542 Tulane Ave, Room 659 New Orleans, LA 70 112
Elyse M. Cornett, PhD
Assistant Professor, Department of Anesthesiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport LA 71103
Abstract
Pediatric anesthesia is a specialized subset of general anesthesia that differs in several important ways from adult anesthesia. This field focuses on the routine care of neonates, infants, children and adolescents and includes a thorough preoperative evaluation, patient and parent preparation, induction of anesthesia, maintenance of anesthesia and emergence from anesthesia There are important differences in anatomy, physiology, pharmacodynamics and pharmacokinetics must be considered and a thorough understanding of the differences between anesthesia in children and adults. In this review these important differences between pediatric anesthesia and adult anesthesia are discussed. The present investigation also describes relevant anatomy, physiology, and pharmacology, and the techniques required for the preparation, intubation, induction of anesthesia, and maintenance of anesthesia in pediatric patients. Finally, newer drug considerations in the pediatric population, such as magnesium sulfate as an adjuvant drug and albuterol for children undergoing tonsillectomy, are reviewed.
