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. Author manuscript; available in PMC: 2015 Aug 1.
Published in final edited form as: Antiviral Res. 2014 May 10;108:25–29. doi: 10.1016/j.antiviral.2014.05.001

Pharmacokinetics and Dose-range Finding Toxicity of a Novel anti-HIV Active Integrase Inhibitor

Vasu Nair a,*, Maurice Okello a, Sanjay Mishra a, Jon Mirsalis b, Kathleen O’Loughlin b, Yu Zhong b
PMCID: PMC4101043  NIHMSID: NIHMS594746  PMID: 24821255

Abstract

Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the “point of no return” in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound 1 and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound 1 in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound 1 exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (> 500 mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.

Keywords: integrase, antiviral drug development, pharmacokinetics, toxicokinetics

While progress in the global therapeutic response to HIV/AIDS has been demonstrable, much still remains to be done in many worldwide communities (Trono et al., 2010; UNAIDS Global Report, 2013; Richman et al., 2009; Este et al., 2010). HIV integrase (Mr 32,000) is a significant target in the discovery and development of anti-HIV therapeutic agents because virus-induced helper T-cell death is suggested as being triggered by viral integration (Cooper et al, 2013). This viral enzyme is essential for HIV replication (Frankel and Young, 1998; Krishnan and Engleman, 2012). Integration of HIV DNA into the host genome requires several steps, including the strand transfer of processed viral cDNA ends into host chromosomal DNA (Frankel and Young, 1998; Haren et al., 1999; Hare et al., 2010).

Research on integrase as a HIV/AIDS therapeutic target has produced three FDA-approved drugs, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) (Sato et al., 2006; Evering and Markowitz 2007; Shimura et al., 2008; Summa et al., 2008; Sato et al., 2009; Min et al., 2010; Min et al., 2011; Katlama and Murphy, 2012). However, there is extensive cross-resistance between RAL and EVG (McColl et al., 2007; Shimura et al., 2008; Goethals el al., 2008). EVG has shown selection of N155H, Q148H/R/K, and G140A/C/S mutations, which are also typical for RAL. Major RAL-associated mutations not selective for EVG were Y143C/R/H (Metifiot et al., 2011). EVG exhibits other resistance mutations like T66I and T66R (Goethals el al., 2008; Shimura et al., 2008; Dicker et al., 2008). Accessory mutations of T66I have not been associated with RAL (McColl and Chen, 2010). DTG demonstrated efficacy against most viral clones that were resistant to RAL and EVG (Canducci et al., 2011; Katlama and Murphy, 2012). Viruses that carry E138K, G140S, or Q148H mutations were not as susceptible to DTG. Integrase mutations T124S/S153F, T124A/S153Y, L101I/T124A/S153F, and S153Y persisted throughout serial passaging of DTG (Katlama and Murphy, 2012; Quashie et al., 2012).

Our search for a HIV-1 integrase inhibitor (Nair and Chi, 2007; Nair et al., 2006; Pommier et al., 2005; Taktakishvili et al., 2000) that would possess significant anti-HIV efficacy and a favorable profile with respect to resistance and drug-drug interactions (Dye and Williams, 2010; Russell et al., 2010), led us to structure-activity studies on inhibitors of the strand transfer step of HIV-1 integrase (Seo et al., 2011). A novel anti-HIV active integrase inhibitor 1 emerged from these studies (Fig. 1). Compound 1 displayed significant in vitro activity against a broad set of HIV-1 subtypes (Keele et al., 2006), as well as against HIV-2 and SIV, and with very low cell cytotoxicity (Okello et al., 2013a). In addition, this compound exhibited a positive drug susceptibility profile against some key clinically-relevant integrase mutations (Fig. 2).

Fig. 1.

Fig. 1

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Integrase inhibitor 1 (left) and its X-ray crystallographic structure (right) depicting its preferred tautomeric form, conformation and intramolecular hydrogen bonding (Bacsa et al., 2013; Okello et al., 2013b).

Fig. 2.

Fig. 2

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Fold change, relative to wild type, in drug susceptibility in MT-4 cells against resistant viruses with some key clinical mutations in integrase: compound 1 – blue; raltegravir – red; elvitegravir – green; dolutegravir – purple. The EC50 against Wild-Type HIV-1 NL4-3 were 63.5, 6.54, 0.82 nM for compound 1, raltegravir and elvitegravir, respectively (Okello et al., 2013a) and 0.71 nM for dolutegravir (Kobayashi et al., 2011). CPE inhibition assays in MT-4 cells (Adachi et al., 1986) were used to generate the antiviral data.

Preclinical pharmacokinetic and toxicokinetic parameters in rats are critical in antiviral drug development because they provide useful initial in vivo information on drug passage and disposition. Of particular significance are data associated with drug exposure, systemic distribution and clearance, drug half-life, percent of drug that reaches circulation, toxic side effects, and initial information on dosing (Szczech, 1996). This communication focuses on preclinical studies of integrase inhibitor 1, the statistical analyses and interpretation of the resulting data, and an insight into the antiviral significance of these findings.

Pharmacokinetics studies (Methods in Supplementary Section) involving iv administration of compound 1 in Sprague Dawley rats at 10 mg/kg dose showed that the mean plasma concentration at the first time-point (Cp) to be 6,403 ng/ml, with a corresponding AUCinf of 3,737 hr*ng/ml (Table 1). In pharmacological terms, the Cp data show that the drug concentration is about 150 fold of the average EC90 (83 nM) for antiviral activity against main Group M subtypes A, B, C and F. Even at the t1/2 (6.1 hr), the drug concentration is significantly higher than the EC90.

TABLE 1.

Pharmacokinetic parameters of compound 1 after iv and po administration in Sprague Dawley rats

Dose
(mg/kg)		 Route aCp or Cmax
(ng/ml)		 Tmax
(hr)		 AUClast
(hr*ng/ml)		 AUCinf
(hr*ng/ml)		 t1/2
(hr)		 MRTlast
(hr)		 Cl
(ml/hr/kg)		 V
(L/kg)		 F
(%)
10 i.v 6403.3(837.6) 0.08(0) 3645.4(713.8) 3737(721.1) 6.1(2.1) 2.2(0.3) 2751.2(586.1) 22.9(4.4) NAb
30 po 463.7(60.7) 1(0.9) 2073.8(778.8) 2148.2(765.2) 3.2(1.1) 4.1(0.9) 2675.9 (0) 12.4(4.3) 19.2(6.9)
100 po 416.7(118) 2.7(1.2) 4273.2(279.9) 4442.2(150.5) 4.5(1.4) 7.3(1.7) 2675.9(0) 17.5(5.5) 11.9(0.4)
300 po 958(187.3) 5.33(2.3) 7809.2(1969.8) 8062.9(1842.4) 4.6(1.7) 6.7(1.1) 2675.9(0) 17.7(6.4) 7.2(1.6)
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a

Cp for iv group; Cmax for po groups

b

NA- not applicable for iv route Data are given as the mean with SD in brackets from three animal experiments in each case

In the po dose groups, the maximal plasma concentration (Cmax) in Sprague Dawley (SD) rats was rapidly reached (Fig. 3). Plasma AUC increased significantly over the entire dose range with increasing drug concentration, suggesting that neither absorption nor first-pass metabolism appeared to be saturable (Table 1). The plasma drug concentration after 8 hr with a po dose of 30 mg/kg was still considerably higher than the average EC90 of compound 1 against key HIV subtypes A, B, C and F. The t1/2 ranged from 3.2 to 4.6 hr. By comparison, the t1/2 for raltegravir in rats at po doses of 40–120 mg/kg was ≤ 1.6 hr (Merck, 2007). The plasma mean residence time (MRT) for compound 1 ranged from 4.1 to 7.3 hr in the po dose groups with a clearance rate (Cl) of 2675 ml/hr/kg. The Cl rate was close to that observed for raltegravir of 2298 ml/hr/kg in rats (Laufer et al., 2009). The apparent volume of distribution (V) of compound 1 was 12.4 L/kg for the 30 mg/kg po dose and was higher than the data for raltegravir (Merck, 2007). Oral bioavailability (F) for the 30 mg/kg dose was 19.2 %, which is lower than that observed for raltegravir 32% (Merck, 2007) and elvitegravir (30–35%) (Gilead, 2011). With respect to dose conversion, the human dose equivalent (CDER, 2005), of the 30 mg/kg po dose of compound 1 from rats to humans, is 294 mg for a single dose for a human weighing 60 kg.

Fig. 3.

Fig. 3

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Plasma concentration of compound 1 in male Sprague Dawley rats after iv and po dose administration of 10, 30, 100 and 300 mg/kg after a single dose in each case. The dosing volume was 5 ml/kg for iv and 10 ml/kg for po.

The objective of the dose-range finding toxicity study was to determine toxic side effects, to identify potential target organs of toxicity, and to determine a no observed adverse effect level (NOAEL) of orally administered compound 1 to adult male and female SD rats (Methods in Supplementary Section). The study was intended to provide preliminary information on the suitability of a proposed safe human dosing. All rats survived until scheduled necropsies. There were no treatment-related effects on body weight at any dose levels tested. The conclusions from these studies were that there were no compound-related clinical pathology findings. There were no statistically significant changes (p ≤ 0.01) in erythropoietic, white blood cell or platelet parameters in male and female rats (Supplementary Tables S1 and S2).

With respect to clinical chemistry parameters (Supplementary Tables S3 and S4), there was no test-article related noteworthy change in these parameters (p ≤ 0.01). Significantly, there were no detectable levels of bilirubin in the urine. Also, there were no treatment-related effects on urobilinogen or other urinalysis parameters (Supplementary Tables S3 and S4). This observation is important because some approved HIV-1 inhibitors such as atazanavir or indinavir affect bilirubin levels in human subjects by inhibiting the bilirubin glucuronidation isoform, UGT1A1. This inhibition leads to the development of hyperbilirubinemia (Michaud et al., 2012, Zucker et al., 2001, Goldsmith and Perry, 2003). Unconjugated bilirubin is highly bound to albumin and can lead to toxicities if the bilirubin/albumin molar ratio exceeds 1:1 (Zhang et al., 2005). We had noted in our earlier studies the lack of UGT substrate activity of compound 1 (Okello, et al., 2013a). In contrast, raltegravir, elvitegravir and dolutegravir are substrates and depend on UGTs for clearance. Combination therapies involving drugs such as atazanavir or indinavir with these approved integrase inhibitors could prove challenging as the inhibition of UGT1A1 by atazanavir or indinavir could lead to accumulation of these drugs with potential toxic drug plasma levels, and would also produce low clearance of bilirubin with accompanying consequences.

Oral administration of compound 1 for 7 consecutive days at doses up to 500 mg/kg/day was well tolerated in rats and produced no adverse treatment-related findings. For instance, the liver function tests to determine the levels of certain marker enzymes, such as ALT and AST, indicated no treatment-related hepatotoxicity (Supplementary Tables S3 and S4). Interestingly, all FDA-approved NRTIs, NNRTIs and PIs are associated with hepatotoxicity (Carr et al., 2001, Sharma, 2011). The NOAEL of compound 1 was determined to be greater than 500 mg/kg/day, which provides a significant exposure margin in antiviral therapeutic applications. Dolutegravir had an NOAEL in adult rats of 50 mg/kg/day (Rhodes et al., 2012) and raltegravir showed an NOAEL of 120mg/kg/day (Merck, 2007), although the dosage and study durations were somewhat different from our studies. The maximum tolerated dose (MTD) for compound 1 is also considered to be greater than 500 mg/kg/day.

The results described in this report provide support that our novel, anti-HIV active integrase inhibitor 1 has additional compelling properties for its further development. Pharmacokinetic studies in rats revealed rapid absorption, a suitable plasma half-life and acceptable bioavailability. Drug exposure increased significantly with increasing drug concentration, indicative of appropriate dose-dependence correlation. The compound exhibited significant extravascular tissue distribution. Serum and urine bilirubin and urobilinogen levels were not affected. There were no adverse treatment-related findings from clinical pathology or clinical chemistry parameters. The preclinical studies also revealed that the NOAEL and MTD parameters were both convincingly high, providing further evidence that there is low potential for toxicity of this antiviral compound with oral administration. Finally, the broad and significant in vitro antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their statistical analysis and pharmacological relevance, provide compelling and critical support for further development of this compound as anti-HIV therapeutic agent.

Supplementary Material

01

Highlights.

  • Anti-HIV active integrase inhibitor with favorable CYP and UGT profiles.

  • Pharmacokinetic data, statistical analyses and interpretation.

  • Toxicokinetics, NOAEL and MTD data analyses and conclusions.

  • Antiviral and pharmacological significance for development as anti-HIV agent.

Acknowledgements

Support of this research by the National Institutes of Health [Grant R01 AI 43181] is gratefully acknowledged. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The animal studies were performed through SRI International, Menlo Park CA, using federal funds from NIAID and Division of AIDS, NIH, under NIAID [contract number HHSN266200700043C]. One of us (VN) also acknowledges support from the Terry Endowment [RR10211184] and from the Georgia Research Alliance Eminent Scholar Award [GN012726].

Glossary

HIV

human immunodeficiency virus

AIDS

acquired immunodeficiency syndrome

PAR

peak area ratio

Cp

plasma concentration at the first time-point

AUCinf

area under the curve up to infinity

t1/2

terminal elimination half-life

Cl

total clearance rate

V

apparent volume of distribution

Cmax

maximal plasma concentration

F

oral bioavailability

iv

intravenous

po

oral

HCT

hematocrit

HOB

hemoglobin

RBC

red blood cell count

RDW

red blood cell distribution width

WBC

white blood cell count

WBC

differential and absolute counts

ANS

total neutrophil

ANB

banded neutrophil

PNS

percentage neutrophil

PNB

percentage banded neutrophil

ALY

total lymphocyte

PLY

percent lymphocyte

AMO

total monocyte

PMO

percent monocyte

AEO

total eosinophil

PEA

percent eosinophil

ABA

total basophil; percent basophil

MCH

mean corpuscular hemoglobin

MCV

mean corpuscular volume

MCC

mean corpuscular hemoglobin concentration

PLC

platelet count

MPV

mean platelet volume

REA (absolute) and RET (percent)

reticulocyte count

TBI

total bilirubin (direct bilirubin, indirect bilirubin)

CRE

creatinine

SOD

sodium

POT

potassium

CHL

chloride

CHO

cholesterol

TRI

triglycerides

GLU

glucose

BUN

blood urea nitrogen

AST

aspartate aminotransferase

ALT

alanine aminotransferase

ALP

alkaline phosphatase

CAL

calcium

PHO

phosphorus

TPR

protein, total

ALB

albumin

AGR

albumin/globulin ratio

GLO

globulin

PBMC

peripheral blood mononuclear cells

NRTIs

nucleoside reverse transcriptase inhibitors

NNRTIs

non-nucleoside reverse transcriptase inhibitors

PIs

protease inhibitors

CPE

cytopathic effect.

Footnotes

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