Drug Penetration to Sanctuary Sites Oral vs. IV Administration

Drug Penetration to Sanctuary Sites Oral vs. IV Administration Courtney V. Fletcher, Pharm.D. Dean, College of Pharmacy Professor, Department of Pharmacy Practice and Division of Infectious Diseases University of Nebraska Medical Center

Clinical Pharmacology Major goals in clinical pharmacology are to describe, quantitate and predict drug effects in humans. Knowledge Requirements Pharmacokinetics: the time course of a drug in humans Pharmacodynamics: relationships between the dose or concentration of drug in the body (exposure) and measured effects Pharmacogenetics: relationships among discrete inherited traits related to drug absorption and disposition, and response

Questions What are the mechanisms and processes of ARV absorption and distribution/penetration into sanctuary sites and tissues? Route of administration Physiologic and pathophysiologic Physiochemical characteristics of the drug Pharmacologic characteristics of the drug What approaches may enhance the PK and PD of ARVs in sanctuary sites and tissue? What considerations are relevant for drug-drug interactions.

Drug Absorption Porter CJH, et al. Nature Reviews Drug Discovery 2007;6:231-48.

Pharmacokinetic Enhancement (boosting): effect on bioavailability Lopinavir 400 mg/ritonavir 50 mg x 1 EC 50 (WT, 50% HS) Lopinavir 400 mg x 1 Sham HL et al. Antimicrob Agents Chemother. 1998;42:3218-3224.

Drug Distribution PET Imaging of Trovafloxacin in Humans Fischman AJ et al. Antimicrob Agents Chemo 1998;42:2048-54.

Drug Distribution Shao J.. Ho RJ. Nanomedicine 2016;11:545-64.

DTG Concentrations in Macaques Characteristic Oral 1 Subcutaneous 2 Plasma Cmax (ng/ml) 2.5 mg/kg sc 1245 3.5 mg/kg oral 963 10 mg/kg oral 1719 Plasma C24 (ng/ml) 2.5 mg/kg sc 1389 3.5 mg/kg oral 97 10 mg/kg oral 209 Ratio Vaginal fluid to Plasma 10 mg/kg oral 0.27 30 mg/kg oral 0.13 Ratio Rectal fluid to Plasma 10 mg/kg oral 0.23 30 mg/kg oral 5.4 1. Del Prete G. AIDS Res Hum Retro 2016;32:163-8. 2. Massud I. J Antimicrob Chemo 2015;70:1473-81.

Rilpivirine plasma concentrations in dogs after IM and SC administration of RPV-LA van t Klooster G, et al. Antimicrob Agents Chemother 2010;54:2042-50.

CAB and RPV plasma concentrations with every 4 or 8 week LA formulation CAB: 400mg q4wk; 600mg q8wk. RVP: 600mg q4wk; 900mg q8wk.

Drug uptake, distribution and retention in the lymph node Shao J.. Ho RJ. Nanomedicine 2016;11:545-64.

Rapid Appearance and Clearance of IDV in Lymph Nodes Oral solution of 14 -C-IDV administered to rats, Peak conc. in lymph appeared at 0.5h after dosing, IDV declined faster in lymph vs. plasma. Lin JH et al. Drug Metab Disp 1996; 24:1111-20.

Drug Absorption via Intestinal Lymphatic System Physicochemical Properties Associated with Lymphatic System Absorption Molecular weight Log P (octanol:water partition) Particle size Long chain TG solubility Trevaskis N, et al. Adv Drug Deliv Rev 2008;60:702-16.

Nanoformulations of ARVs Subcutaneous administration of LPV, RTV and TFV packaged together in a lipid nanoparticle (LNP) or as native drug to 4 macaques. Concentrations are ratios of the LNP to native formulation. Time Lopinavir Ritonavir Tenofovir Plasma drug exposure 0-168h 18.2 14.0 7.0 Intracellular drug concentrations 168h > 8 >132 >25 Inguinal LN intracellular drug concentration 24h > 485 50.5 0.7 Freeling JP Ho R. AIDS 2014;28:2625-2631.

Tissue Distribution of TFV after Oral TDF or Tenofovir Alafenamide * Tissue or Fluid TDF conc TAF conc TAF:TDF Kidney 88 80 0.9 Lungs 0.50 4.34 8.2 Inguinal lymph nodes 0.28 4.12 15 Spleen 0.63 8.13 12.8 Brain < LOD < LOD - Ileum 0.50 4.61 9.2 Prostate 0.24 2.14 9.1 Bone marrow 0.20 2.05 10.2 * Male beagle dogs. Lee, W.A. et al. Antimicrob Agents Chemo 2005;49:1898.

Transporter Localization in Testicular Tissue Huang Y,.. Fletcher CV,.. Bendayan R. J Antimicrob Chemother 2016,71)7):1954-65

Lymphoid Fibrosis Occurs and Persists with Antiretroviral Therapy Greater LN collagen deposition has previously been associated with poorer CD4 cell response to ART (Schacker TW, AIDS 2005;19:2169-71). Significantly higher collagen deposition occurred in all HIV-infected persons, including elite controllers, vs. HIV uninfected persons. Collagen deposition in LT changes architecture & function and ultimately causes progressive loss of naïve T cells. Sanchez JL et al. J Infect Dis 2015;211:1068-75. VL < 75cpm in 44/45 (98%)

SIV Dynamics by Whole Body ImmunoPET In ART treated, aviremic macaques, all organs exhibited decreased uptake of the immunopet probe. Residual signal remained, however, in the colon, spleen, male genital tract and individual lymph nodes. Santangelo PJ et al. Nature Methods 2015; March 9.

Compartmental differences in RPV levels following a single IM dose of RPV-LA Vaginal fluid to plasma ratios were >1; endocervical and rectal fluid ratios were <1. Vaginal and ectocervical tissue to plasma ratios were <1 (0.44-0.72 and 0.42-0.77, respectively). RPV rectal tissue to plasma ratios in women were 1.10 1.22, and were 1.5-2.5 fold higher than vaginal or cervical tissue.

PKPD Correlations between Explant Infections and RPV Concentrations A significant PKPD relationship was observed for rectal tissue and fluid explant infection models. No relationships were found for cervical or vaginal models. McGowan I, et al. Lancet HIV 2016; online Sept 15.

Rifampin decreases cabotegravir concentrations after oral administration Ford S et al. HIV Clin Pharm 2016. Abstract O-18

Levonorgestrel PKPD with EFV-based ART EFV reduced levonorgestrel concentrations 47-57% after 24-48 weeks. 3 unintended pregnancies occurred (3/20, 15%) in the EFV recipients, but none in the NVP or ART naïve groups. Scarsi K. Clin Infect Dis 2016; 62:675-82.

ARV Penetration: Mechanisms & Determinants Our knowledge of mechanisms and determinants of drug uptake, distribution and retention at the site of action is poor. Known factors include: Physiology and Pathophysiology: Portal vein vs. lymph blood flow is 500:1; therefore, most absorbed drugs are preferentially diverted to portal blood. Lymph node fibrosis; collagen deposition and resulting fibrosis are correlated with progression to AIDS and less immune reconstitution. Physicochemical characteristics of the drug: Greater lymphatic system penetration is associated with hi molecular weight, larger particle size, log P value > 5, hi long chain TG solubility. Pharmacologic characteristics: Protein binding; ARV substrate susceptibility to membrane transporters and CYPs noting heterogenous distribution and expression, e.g. P-gp increases from duodenum to ileum; CYP3A4 decreases from duodenum to colon.