Long-acting Pharmacokinetics Research Articles

P-314. A Retrospective Review of Long-Acting Lipoglycopeptide Utilization at a VA Tertiary Teaching Medical Center

Abstract Background Dalbavancin and oritavancin are long-acting lipoglycopeptides (LA-LGPs) approved by the Food and Drug Administration (FDA) for acute skin and soft tissue infections (ASSTIs). With their long-acting pharmacokinetics and broad activity against gram-positive bacteria, LA-LGPs are ideal options for patients with serious infections, such as bone, joint, and bloodstream, who (1) require prolonged antimicrobial therapy, (2) are not candidates for long-term intravascular catheter access, (3) prefer to avoid hospital admission, and/or (4) need early discharge. Methods A retrospective chart review was conducted on patients ages older than 18 with a medication order of dalbavancin or oritavancin from September 2020- August 2023 at the Atlanta VA Medical Center. Patients were excluded if the patient did not have an active infection or a LA-LGP was ordered but not administered. Pertinent demographic, clinical, and microbiological data were collected from the patient’s medical record. Results Resolution of infection in 3 months with LA-LGPs was found to be 76% (35/46) effective in lower extremity osteomyelitis and 74% (72/98) effective for all indications. The mean total length of stay (inpatient) after LA-LGP infusion was 3.9 days. The most common adverse events were nausea and vomiting, which occurred at a rate of 6.1% (6/98). Conclusion The utilization of LA-LGPs showed to be effective in infection resolution in a 3-month period in majority of patients. Specifically, lower extremity osteomyelitis, a non-FDA approved use, showed promising results in resolution of infection. The use of LA-LGPs can be beneficial in shortening hospital length of stay and prevention of hospitalizations with minimal adverse events. This can possibly lead to decreased health care cost and hospital acquired infections. In all, the use of LA-LGPs has significant potential use in other serious infections other than ASSTIs with a variety of benefits from the patient and healthcare perspective. Disclosures All Authors: No reported disclosures

Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

A novel formulation enabled transformation of 3-HIV drugs tenofovir-lamivudine-dolutegravir from short-acting to long-acting all-in-one injectable.

To develop an injectable dosage form of the daily oral HIV drugs, tenofovir (T), lamivudine (L), and dolutegravir (D), creating a single, complete, all-in-one TLD 3-drug-combination that demonstrates long-acting pharmacokinetics. Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3-HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP . TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina ). Following single-dose TLD-in-DcNP , all drugs exhibited long-acting profiles in NHP plasma with levels that persisted for 4 weeks above predicted viral-effective concentrations for TLD in combination. Times-to-peak were within 24 hr in all NHP for all drugs. Compared to a free-soluble TLD, TLD-in-DcNP provided exposure enhancement and extended duration 7.0-, 2.1-, and 20-fold as AUC boost and 10-, 8.3-, and 5.9-fold as half-life extension. Additionally, DcNP may provide more drug exposure in cells than plasma with PBMC-to-plasma drug ratios exceeding one, suggesting cell-targeted drug-combination delivery. This study confirms that TLD with disparate properties can be made stable by DcNP to enable TLD concentrations of 4 weeks in NHP. Study results highlighted the potential of TLD-in-DcNP as a convenient all-in-one, complete HIV long-acting product for clinical development.

Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture

Drug-combination nanoparticles (DcNP) allow the formulation of multiple HIV drugs in one injectable. In nonhuman primates (NHP), all drugs in DcNP have demonstrated long-acting pharmacokinetics (PK) in the blood and lymph nodes, rendering it suitable for a Targeted Long-acting Antiretroviral Therapy (TLC-ART). To support the translation of TLC-ART into the clinic, the objective is to present a physiologically based PK (PBPK) model tool to control mechanisms affecting the rather complex DcNP-drug PK. Two species contribute simultaneously to the drug PK: drugs that dissociate from DcNP (Part 1) and drugs retained in DcNP (Part 2, presented separately). Here, we describe the PBPK modeling of the nanoparticle-free drugs. The free-drug model was built on subcutaneous injections of suspended lopinavir, ritonavir, and tenofovir in NHP, and validated by external experiments. A novelty was the design of a lymphatic network as part of a whole-body PBPK system which included major lymphatic regions: the cervical, axillary, hilar, mesenteric, and inguinal nodes. This detailed/regionalized description of the lymphatic system and mononuclear cells represents an unprecedented level of prediction that renders the free-drug model extendible to other small-drug molecules targeting the lymphatic system at both the regional and cellular levels.

Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.

The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.

Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101

TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive. Therefore, an intravenous study of TLC-ART 101 in nonhuman primates was conducted to elucidate the degree of association of drugs in vivo, estimate subcutaneous bioavailability, and refine a mechanism-based pharmacokinetic (MBPK2) model. The MBPK2 model considers TLC-ART 101 systemic drug clearances, nanoparticle-associated/dissociated species, more detailed mechanisms of lymphatic first-pass retention of associated-drugs after subcutaneous administrations, and the prediction of drug concentration time-courses in lymph node mononuclear cells. For all 3 drugs, we found a high association with the nanoparticles in plasma (>87% lopinavir-ritonavir, 97% tenofovir), and an incomplete subcutaneous bioavailability (<29% lopinavir-ritonavir, 85% tenofovir). As hypothesized by the MBPK2 model, the incomplete SC bioavailability observed is due to sequestration into a lymphatic node depot after subcutaneous absorption (unlike most intramuscular nanodrug products having near-to-injection depots), which contributes to long-acting profiles detected in plasma and target cells. This combined experimental and modeling approach may be applicable for the clinical development of other long-acting drug-combination injectables.

Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation

Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs—hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)—stabilized by lipid excipients in a nanosuspension. A single subcutaneous (SC) injection of this first-generation formulation of drug combination nanoparticles (DcNPs), named TLC-ART101, provided persistent ARV levels in macaque lymph node mononuclear cells (LNMCs) for at least 1 week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2 weeks, demonstrating long-acting pharmacokinetics for all three drugs. In addition, the lymphocyte-targeting properties of this formulation were demonstrated by the consistently higher intracellular drug concentrations in LNMCs and PBMCs versus those in plasma. To provide insights into the complex mechanisms of absorption and disposition of TLC-ART101, we constructed novel mechanism-based pharmacokinetic (MBPK) models. Based upon plasma PK data obtained after single administration of TLC-ART101 (DcNPs) and a solution formulation of free triple-ARVs, the models feature uptake from the SC injection site that respectively routes free and nanoparticle-associated ARVs via the blood vasculature and lymphatics, and their eventual distribution into and clearance from the systemic circulation. The models provided simultaneous description of the complex long-acting plasma and lymphatic PK profiles for all three ARVs in TLC-ART101. The long-acting PK characteristics of the three drugs in TLC-ART101 were likely due to a combination of mechanisms including: (1) DcNPs undergoing preferential lymphatic uptake from the subcutaneous space, (2) retention in nodes during lymphatic first-pass, (3) subsequent slow release of ARVs into blood circulation, and (4) limited extravasation of DcNP-associated ARVs that resulted in longer persistence in the circulation.

CD101, a long-acting echinocandin, and comparator antifungal agents tested against a global collection of invasive fungal isolates in the SENTRY 2015 Antifungal Surveillance Program

CD101 is a novel echinocandin with exceptional chemical stability and long-acting pharmacokinetics. The activity of CD101 and comparators was evaluated using CLSI broth microdilution methods against 713 invasive fungal isolates, including 589 Candida spp. (6 species), 14 C. neoformans, 97 A. fumigatus and 13 A. flavus species complex collected worldwide during 2015. All C. tropicalis, C. krusei and C. dubliniensis, 99.7% of C. albicans and 98.3% of C. glabrata were inhibited by ≤0.12 µg/mL of CD101, and these isolates were susceptible/wild type to other echinocandins using CLSI clinical breakpoint and epidemiological cutoff value (ECV) interpretive criteria. C. parapsilosis displayed higher MIC values (range 0.25–2 µg/mL), but similar results were observed for other echinocandins. One C. glabrata and one C. albicans with CD101 MIC value at 1 and 0.25 µg/mL possessed F625S and S645P alterations on FKS1, respectively. These isolates also displayed elevated MIC values for at least one clinically available echinocandin. Fluconazole resistance was noted for 6.6% of C. glabrata and 3.6% C. parapsilosis. Echinocandins had limited activity against C. neoformans. CD101 activity against A. fumigatus and A. flavus (MEC ≤0.03 µg/mL) was comparable to other echinocandins (MEC ≤0.03 µg/mL). These moulds had MIC values below ECVs for the mould-active azoles. CD101 was as active as other echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable as less frequent dosing of this agent should facilitate shorter and more cost-effective hospital stays, improve compliance for outpatients, and provide more convenient outpatient prophylaxis.

Efficacy of CD101, a Novel Echinocandin, in Mouse Models of Aspergillosis and Azole-Resistant Disseminated Candidiasis

Background: CD101 is a novel echinocandin with long-acting pharmacokinetics and exceptional stability in development for prevention and treatment of serious fungal infections. The in vivo efficacy of CD101 was evaluated using neutropenic mouse models of azole-resistant candidiasis and aspergillosis.Methods: An azole-resistant strain of Candida albicans (R357; resistant to fluconazole [Flu], voriconazole, and posaconazole but susceptible to amphotericin B [AmB] and echinocandins) isolated from human blood was used for the mouse candidiasis model. A test strain of Aspergillus fumigatus (ATCC 13073) was used for the mouse aspergillosis model. Mice were rendered neutropenic by cyclophosphamide and then infected by injections of C. albicans (105 CFU/mouse) or A. fumigatus (104 CFU/mouse) into the tail vein. Test articles were administered starting 2 hours after infection. In the mouse candidiasis model, groups of 5 mice each received one dose of AmB (3 mg/kg IV), Flu (20 mg/kg orally), or CD101 (3, 10 or 30 mg/kg by intraperitoneal administration [IP]). After 72 hours post-infection, mice were euthanized and C. albicans counts in kidney tissue (CFU/g) were measured. In the mouse aspergillosis model, groups of 10 mice each received one dose ofAmB (2 mg/kg IP) or CD101 (2 mg/kg IV and IP). Survival was monitored daily for 10 days. Differences between vehicle and test article groups were assessed for significance by one-way ANOVA followed byDunnett's test and Fisher's Exact test in the candidiasis and aspergillosis models, respectively.Results: One dose of CD101 3 mg/kg produced a >99.9% (or > 3-log; P<0.001) reduction in C. albicans CFU compared with vehicle through at least 72hours post-dose following a single IP dose.AmB showed similar, albeit less robust, efficacy (>99% or >2-log reduction in CFU; P<0.05), whereas fluconazole was less efficacious (83.9% or <2-log reduction in CFU). In the aspergillosis model, CD101 administered 2 mg/kg IV or IP showed similar efficacy to that ofAmB 2 mg/kg IP, both with significantly longer survival than vehicle (P<0.05; Figure).Conclusions: A single dose of CD101 3 mg/kg produced significant reduction in C. albicans burden compared with vehicle (P<0.001) in the neutropenic mouse model of azole-resistant candidiasis, demonstrating efficacy comparable, if not better, to that of AmB at the same dose. One dose of CD101 also demonstrated efficacy in the mouse model of aspergillosis. These data support the continued development of CD101 for treatment of serious infections caused by Candida, including azole-resistant strains, and Aspergillus spp. [Display omitted] DisclosuresOng:Cidara Therapeutics, Inc.: Employment. Bartizal:Cidara Therapeutics, Inc.: Employment, Other: Stockholder. Miesel:Eurofins Panlabs: Employment; Cidara Therapeutics, Inc: Research Funding.

Crimson carrier, A long‐acting contrast agent for in vivo near‐infrared imaging of injured and diseased muscle

The near-infrared wavelengths (700-900 nm) are the most suitable optical window for light penetration and deep tissue imaging in small animals. Herein we report a near-infrared fluorescent contrast agent, crimson carrier, which acts as a blood pool contrast agent to detect and quantify injury and disease in live animals. After determining the excitation-emission spectra and pharmacokinetics, crimson carrier was injected into myoinjured mice to monitor their recovery. Crimson carrier was also used to image transgenic mice with spontaneous tumors. Crimson carrier has maximal excitation and emission wavelengths of 745 nm and 820 nm, respectively. Elimination occurs predominantly via urinary excretion. We demonstrate the utility of this contrast agent for serial imaging of traumatized muscle as well as muscle tumors. The unique long-acting pharmacokinetics and urinary excretion route characteristics make crimson carrier a contrast agent of choice for the visualization of tumors and injured muscle or other tissues in live animal studies.

Long-Acting Insulin Analogs and the Risk of Diabetic Ketoacidosis in Children and Adolescents With Type 1 Diabetes

OBJECTIVETo investigate if long-acting insulin analogs decrease the risk of diabetic ketoacidosis (DKA) in young individuals with type 1 diabetes.RESEARCH DESIGN AND METHODSOf 48,110 type 1 diabetic patients prospectively studied between 2001 and 2008, the incidence of DKA requiring hospitalization was analyzed in 10,682 individuals aged ≤20 years with a diabetes duration of ≥2 years.RESULTSThe overall rate of DKA was 5.1 (SE ± 0.2)/100 patient-years. Patients using insulin glargine or detemir (n = 5,317) had a higher DKA incidence than individuals using NPH insulin (n = 5,365, 6.6 ± 0.4 vs. 3.6 ± 0.3, P < 0.001). The risk for DKA remained significantly different after adjustment for age at diabetes onset, diabetes duration, A1C, insulin dose, sex, and migration background (P = 0.015, odds ratio 1.357 [1.062–1.734]).CONCLUSIONSDespite their long-acting pharmacokinetics, the use of insulin glargine or detemir is not associated with a lower incidence of DKA compared with NPH insulin.