Voclosporin: a novel calcineurin inhibitor for the treatment of lupus nephritis.

INTRODUCTION: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus. Standard-of-care immunosuppressive therapies achieve poor complete renal response (CRR) rates, with considerable toxicity. This article reviews voclosporin, a novel oral calcineurin inhibitor (CNI) approved for treatment in adults with active LN by the US Food and Drug Administration (the FDA) in January 2021. AREAS COVERED: This review summarizes the chemical properties, pharmacokinetics, and pharmacodynamics of voclosporin, and its efficacy and safety in LN, based on literature review covering PubMed searches, manufacturers' websites, and documents produced by the FDA. EXPERT OPINION: Voclosporin is a CNI with a consistent pharmacokinetic-pharmacodynamic relationship resulting from enhanced calcineurin binding and reduced drug and metabolite load. This profile permits therapeutic efficacy in LN at a dose associated with relatively low calcineurin inhibition, and therefore a potentially improved safety profile. Pivotal trials demonstrated a significant benefit of adding voclosporin to standard therapy, with rapid reduction in proteinuria, and a clinically meaningful and significantly higher CRR rate at 1 year. At approved doses for LN, potential advantages of voclosporin versus historical experience with CNIs include lack of need for therapeutic drug monitoring, benign metabolic, lipid and electrolyte profile, and no impact on mycophenolate mofetil levels.

Brain uptake and distribution patterns of 2-hydroxypropyl-ß-cyclodextrin after intrathecal and intranasal administration.

OBJECTIVES: Cyclodextrins are increasingly used therapeutically. For example, 2-hydroxypropyl-ß-cyclodextrin (kleptose) is used for the treatment of Niemann-Pick disease. Kleptose crosses the blood-brain barrier poorly, in part because of a central nervous system (CNS)-to-blood (efflux) transporter, and so is administered by the intrathecal (IT) route in the treatment of Niemann-Pick disease. METHODS: Here, we evaluated the uptake and distribution of kleptose by the brain and spinal cord after intranasal (IN) or IT delivery. KEY FINDINGS: Kleptose distributed to all regions of the brain and spinal cord after IN administration, with only 3.27% of the administered dose entering the bloodstream. Intrathecal delivery produced levels in the whole brain about 40 times higher than intranasal administration and about 20 times higher than previously found after intravenous administration. About 70-90% of the IT dose rapidly entered the bloodstream, in part because of the previously described efflux transporter. The uptake by CNS after IN and IT was both non-saturable. The uptake by the olfactory bulb, hypothalamus and pons-medulla was favoured by all routes of administration. CONCLUSIONS: Kleptose was taken up by all regions of the CNS after either IN or IT administration, but IN administration resulted in only a fraction of the uptake of the IT route.

Modest Blood-Brain Barrier Permeability of the Cyclodextrin Kleptose: Modification by Efflux and Luminal Surface Binding.

Cyclodextrins (CDs) have a variety of uses from acting as excipients to aiding the ability of lipid soluble drugs to cross the blood-brain barrier (BBB). They are being investigated as an active pharmaceutical ingredient, most recently for the treatment of Niemann-Pick disease, a lysosomal storage disease. Cyclodextrins are helpful in animal models and human subjects/patients afflicted with Neimann-Pick disease, including improving the neurologic component of the disease. The improvement in brain disease by intravenous administration implies that CDs can cross the BBB; however, there are only a few studies that have directly addressed this. In the current studies, multiple-time regression analysis indicated that 2-hydroxypropyl-ß-cyclodextrin [Kleptose (Klep)] radioactively labeled with 14C (C-Klep) crossed the BBB at a slow rate by a nonsaturable mechanism consistent with transcellular diffusion. However, the rate of transport varied greatly by the brain region with no detectable uptake by the spinal cord; additionally, many regions rapidly reached equilibrium between the brain and blood. The presence of a brain-to-blood efflux system was also detected and much of the C-Klep did not completely cross the BBB, but loosely adhered to the luminal surface of brain endothelial cells. Peripheral tissues also took up C-Klep, with the kidney taking up the most, which is consistent with renal clearance. In conclusion, we demonstrated minimal uptake of the ß-cyclodextrin Kleptose by the brain with accumulation being affected by efflux and reversible luminal binding. SIGNIFICANCE STATEMENT: This cyclodextrin, which produces therapeutic effects on the central nervous system after peripheral administration, penetrates the BBB poorly. Uptake by the brain to a therapeutic level will likely be difficult to achieve without giving high peripheral doses, bypassing the BBB, or otherwise altering penetration into the brain.

Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs.

PURPOSE: NSC 743400 is a novel synthetic indenoisoquinoline analog under development as an anticancer agent. It is a potent topoisomerase I inhibitor with potential therapeutic advantages over FDA-approved camptothecin derivatives. In preparation for clinical development of NSC 743400, we determined the pharmacokinetics after administration to rats and dogs. METHODS: NSC 743400 was administered intravenously at a dose of 12 or 24 mg/m(2) to rats (single bolus) or 10, 50, 100, 215, 430, or 646 mg/m(2) (intravenous infusion) or 860 or 1720 mg/m(2) (orally) to dogs. RESULTS: Intravenously administered NSC 743400 was eliminated from both species with an estimated t 1/2 of 2-5 h in rat and 6-14 h in dog. Elimination t 1/2 increased with dose in dog. Area under the plasma concentration-versus-time curve (AUC) was comparable in both species, at about 300-400 h ng/mL for the approximately 10 mg/m(2) dose groups. Overall, AUC values increased proportionally with dose for both species but had evidence of more than proportional exposure at the highest doses. Oral dosing resulted in variable drug absorption. CONCLUSIONS: The pharmacokinetic data were used to plan first-in-human clinical trials.

Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.

Decitabine (5-aza-2'-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and ß-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼ 10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.

Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.

PURPOSE: The cytidine analogs 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase 1 (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application. EXPERIMENTAL DESIGN: Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity, and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated patients with MDS (n = 90) and cytarabine-treated patients with acute myeloid leukemia (AML) (n = 76). RESULTS: By high-performance liquid chromatography (HPLC), plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females than in males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared with high S-phase fraction disease (e.g., MDS vs. AML), because in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female patients with MDS treated with 5-azacytidine/decitabine. CONCLUSIONS: Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.

Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine.

The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2µM administered 2×/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.

IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8+ T effector memory population in peripheral blood.

IL-15 promotes activation and maintenance of natural killer (NK) and CD8(+) T effector memory (T(EM)) cells, making it a potential immunotherapeutic agent for the treatment of cancer and immunodeficiency states. Here we report the immunologic effects of 3 different IL-15 dosing strategies in Rhesus macaques. IL-15 at a dose of 20 µg/kg/d administered by continuous intravenous infusion for 10 days resulted in a massive (100-fold) expansion of CD8(+) T(EM) cells in the peripheral blood. In contrast, the administration of 20-40 µg/kg/d of IL-15 by subcutaneous injection resulted in a more modest (10-fold) expansion of CD8(+) T(EM) cells. NK expansion was similar in both the continuous intravenous and daily subcutaneous treatment groups. The observation that IL-15 administered by continuous intravenous infusion is able to induce markedly greater expansions of CD8(+) T(EM) cells than the same dose administered by other routes may have important implications for clinical development of this cytokine.

Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone.

Previous studies utilizing an ex vivo porcine model of intestinal ischemic injury demonstrated that prostaglandin (PG)E(2) stimulates repair of mucosal barrier function via a mechanism involving Cl(-) secretion and reductions in paracellular permeability. Further experiments revealed that the signaling mechanism for PGE(2)-induced mucosal recovery was mediated via type-2 Cl(-) channels (ClC-2). Therefore, the objective of the present study was to directly investigate the role of ClC-2 in mucosal repair by evaluating mucosal recovery in ischemia-injured intestinal mucosa treated with the selective ClC-2 agonist lubiprostone. Ischemia-injured porcine ileal mucosa was mounted in Ussing chambers, and short-circuit current (I(sc)) and transepithelial electrical resistance (TER) were measured in response to lubiprostone. Application of 0.01-1 microM lubiprostone to ischemia-injured mucosa induced concentration-dependent increases in TER, with 1 microM lubiprostone stimulating a twofold increase in TER (DeltaTER = 26 Omega.cm(2); P < 0.01). However, lubiprostone (1 microM) stimulated higher elevations in TER despite lower I(sc) responses compared with the nonselective secretory agonist PGE(2) (1 microM). Furthermore, lubiprostone significantly (P < 0.05) reduced mucosal-to-serosal fluxes of (3)H-labeled mannitol to levels comparable to those of normal control tissues and restored occludin localization to tight junctions. Activation of ClC-2 with the selective agonist lubiprostone stimulated elevations in TER and reductions in mannitol flux in ischemia-injured intestine associated with structural changes in tight junctions. Prostones such as lubiprostone may provide a selective and novel pharmacological mechanism of accelerating recovery of acutely injured intestine compared with the nonselective action of prostaglandins such as PGE(2).