Canine orosomucoid (alpha-1 acid glycoprotein) variants and their influence on drug plasma protein binding.

Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated.

Oral delivery of indinavir using mPEG-PCL nanoparticles: preparation, optimization, cellular uptake, transport and pharmacokinetic evaluation.

Introduction: Indinavir (IDV) is a potent HIV protease inhibitor used in the treatment of human immunodeficiency virus (HIV). IDV is a weak base with limited aqueous solubility in its unprotonated form; therefore, solubility of IDV in the gastrointestinal tract fluids is the rate-limiting step of its absorption and onset of action. However, in many cases, drugs are not absorbed well in the gastrointestinal tract; polymer nanoparticles were recognized as an effective carrier system for drug encapsulation and are now studied as a vehicle for oral delivery of insoluble compounds. Preparation of methoxy poly (ethylene glycol)-poly (e-caprolactone) (mPEG-PCL) nanoparticles is among the strategies to overcome low bioavailability of drugs with poor aqueous solubility. Materials and method: The structure of the copolymers was characterized using 1H NMR, FTIR, DSC and GPC techniques. IDV loaded mPEG- PCL nanoparticles prepared by emulsification solvent evaporation method were optimized using D-optimal experimental design and were characterized by various techniques such as DLS, DSC, XRD, AFM and SEM. Using Caco-2 cells as a cellular model, we studied the cellular uptake and transport. Results: In vivo pharmacokinetic studies were performed in rats. The plasma AUC (0-t), t1/2 and Cmax of IDV-mPEG-PCL NPs were increased by 5.30, 5.57 and 1.37 fold compared to the IDV solution, respectively. Conclusion: The results of this study are promising for the use of biodegradable polymeric nanoparticles to improve oral drug delivery.

Neuropharmacokinetic evaluation of lactoferrin-treated indinavir-loaded nanoemulsions: remarkable brain delivery enhancement.

OBJECTIVE: Indinavir (IDV), an antiretroviral protease inhibitor used in treatment of HIV infection, has limited entry into brain due to efflux by the P-glycoprotein presented in blood-brain barrier. The aim of present study was to develop lactoferrin-treated nanoemulsion containing indinavir (Lf-IDV-NEs) for delivery to brain. METHODS: Indinavir-loaded nanoemulsions (IDV-NEs) were prepared by high-speed homogenization method, and then lactoferrin was coupled to IDV-NEs by water soluble EDC method. RESULTS: The hydrodynamic diameters, polydispersity index, and zeta potential of IDV-NEs were 112 ± 3.5 nm, 0.20 ± 0.02, and -33.2 ± 2.6 mV, respectively. From in vivo studies in animal model of rats, the AUC0-4 h of brain concentration-time profile of IDV-NEs and Lf-IDV-NEs were 1.6 and 4.1 times higher than free drug, respectively. The brain uptake clearance of IDV-NEs and Lf-IDV-NEs were, interestingly, 393- and 420-times higher than the free drug. CONCLUSIONS: It can be concluded that applying both lactoferrin-treated and non-treated nanoemulsions clearly leads to significant brain penetration enhancement of indinavir, an effect which is more pronounced in the case of Lf-IDV-NEs with the higher drug residence time in brain.

Indinavir-Loaded Nanostructured Lipid Carriers to Brain Drug Delivery: Optimization, Characterization and Neuropharmacokinetic Evaluation.

PURPOSE: As an anti-retroviral Protease Inhibitor (PI), Indinavir (IDV) is part of the regimen known as Highly Active Anti-Retroviral Therapy (HAART) widely used for Human Immunodeficiency Virus (HIV) infection. The drug efficiency in treatment of the brain manifestations of HIV is, however, limited which is mainly due to the efflux by P-glycoprotein (P-gp) expressed at the Blood-Brain Barrier (BBB). METHODS: To overcome the BBB obstacle, NLCs were used in this study as carriers for IDV, which were optimized through two steps: a "one-factor-at-a-time" screening followed by a systematic multiobjective optimization. Spherical smooth-surfaced Nanoparticles (NPs), average particle size of 161.02±4.8 nm, Poly-Dispersity Index (PDI) of 0.293±0.07, zeta potential of -40.62±2.21 mV, entrapment efficiency of 93±1.58%, and loading capacity of 9.15±0.15% were obtained after optimization which were, collectively, appropriate in terms of the objective of this study. RESULT: The surface of the optimized NPs was, then, modified with human Transferrin (TR) to improve the drug delivery. The particle size, zeta potential, and PDI of the TR-modified NLCs were 185.29±6.7nm, -28.68±3.37 mV, and 0.247±0.06, respectively. The in vitro release of IDV molecules from the NPs was best fitted to the Weibull model indicating hybrid diffusion/erosion behavior. CONCLUSION: As the major in vivo findings, compared to the free drug, the NLCs and TR-NLCs displayed significantly higher and augmented concentrations in the brain. In this case, NLC and TR-NLC were 6.5- and 32.75-fold in their values of the brain uptake clearance compared to free drug.

The In Vitro and In Vivo Effects of Hypoxis hemerocallidea on Indinavir Pharmacokinetics: Modulation of Efflux.

Hypoxis hemerocallidea (African potato) is a popular medicinal plant that has been used traditionally for the treatment of various disorders. Some HIV/AIDS patients use this traditional medicine together with their antiretroviral therapy. This study aimed to determine the impact of selected H. hemerocallidea materials (i.e., a commercial product, an aqueous extract, and biomass reference plant material) on the bidirectional permeability of indinavir across Caco-2 cell monolayers as well as the bioavailability of indinavir during an acute, single administration study in Sprague-Dawley rats. All of the selected H. hemerocallidea test materials demonstrated inhibition effects on indinavir efflux across Caco-2 cell monolayers, albeit to different extents. An increase in the bioavailability of indinavir was obtained in vivo when administered concomitantly with the H. hemerocallidea materials, albeit not statistically significantly. The change in bioavailability directly correlated with the in vitro permeability results. It can therefore be concluded that the change in permeability and bioavailability of indinavir was caused by efflux inhibition and this effect was dependent on the type of H. hemerocallidea material investigated, which was found to be in the following order: commercial product > aqueous extract > reference plant material. The clinical significance of the combined effect of efflux and metabolism inhibition by H. hemerocallidea should be determined in another in vivo model that expresses the cytochrome P450 3A4 enzyme.

Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters.

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.

Differences in the Prediction of Area Under the Curve for a Protease Inhibitor Using Trough Versus Peak Concentration: Assessment Using Published Pharmacokinetic Data for Indinavir.

In the present day antiretroviral therapy, Ctrough is a key tool for efficacy assessment. The present work explored the feasibility of using Ctrough or Cmax in the area under the concentration-time curve (AUC) prediction of indinavir. A simple unweighted linear regression model was developed to describe the relationship between Cmax versus AUC (r = 0.8101, P < 0.001) and Ctrough versus AUC (r = 0.8127, P < 0.001) for indinavir. The regression lines were used to predict the AUC values from literature Cmax or Ctrough data of indinavir in HIV and healthy subjects. The fold difference, defined as the quotient of the observed and predicted AUC values, was evaluated along with statistical comparison, including root mean square error (RMSE) prediction for the 2 models. The correlation between Cmax versus AUC and Ctrough versus AUC was established. Majority of the predicted values for Cmax versus AUC were within 0.75- to 1.5-fold differences. However, the Ctrough versus AUC model showed larger variability with approximately one-third of the predictions within 0.75- to 1.5-fold differences. The r value and %RMSE for observed versus predicted AUC for Ctrough (r = 0.5925, n = 65, P < 0.001, and RMSE: 67%) were inferior to the Cmax (r = 0.8773, n = 86, P < 0.001, and RMSE: 46%). In conclusion, Cmax versus AUC and Ctrough versus AUC relationships were established for indinavir showing the utility of a single concentration time point for therapeutic drug monitoring purpose. The Cmax model for indinavir may be more relevant for AUC prediction as determined by the statistical criteria.

Gastrointestinal dissolution, supersaturation and precipitation of the weak base indinavir in healthy volunteers.

This study investigated the impact of relevant gastrointestinal conditions on the intraluminal dissolution, supersaturation and precipitation behavior of the weakly basic drug indinavir. The influence of (i) concomitant PPI intake and (ii) the nutritional state on the gastrointestinal behavior of indinavir was assessed in order to identify the underlying mechanisms responsible for previously reported interactions. Five healthy volunteers were recruited into a crossover study containing the following arms: fasted state, fed state and fasted state with concomitant proton pump inhibitor (PPI) use. In each condition, one Crixivan® capsule (400mg indinavir) was orally administered with 240mL of water. Gastric and duodenal fluids, aspirated as a function of time, were monitored for total and dissolved indinavir concentrations on a UPLC-MS/MS system. Indinavir's thermodynamic solubility was determined in individual aspirates to evaluate supersaturation. The bioaccessible fraction of indinavir in aspirated duodenal fluids was determined in an ex vivo permeation experiment through an artificial membrane. A nearly complete dissolution of indinavir in the fasted stomach was observed (90±3%). Regardless of dosing conditions, less indinavir was in solution in the duodenum compared to the stomach. Duodenal supersaturation was observed in all three testing conditions. The highest degrees of duodenal supersaturation (6.5±5.9) were observed in the fasted state. Concomitant PPI use resulted in an increased gastric pH and a smaller fraction of indinavir being dissolved (58±24%), eventually resulting in lower intestinal concentrations. In fed state conditions, drug release from the capsule was delayed and more gradually, although a similar fraction of the intragastric indinavir dissolved compared to the fasted state (83±12%). Indinavir was still present in the lumen of the duodenum three hours after oral administration, although it already reached 70% (on average) of the fasted state concentrations (expressed as AUC0-3h). Based on a 2-h permeation experiment, the bioaccessible fraction of indinavir was 2.6-fold lower in a fed state sample compared to a fasted state sample. Our data indicate that the reported reduction in indinavir's bioavailability after concomitant PPI administration is caused by an elevated gastric pH resulting in less indinavir in solution in the stomach and, subsequently, reduced duodenal concentrations. In fed state conditions, however, intestinal micellar entrapment of indinavir appeared to cause the reported reduced bioavailability, regardless of duodenal concentrations.

Evaluation of Isolated Fractions of Aloe vera Gel Materials on Indinavir Pharmacokinetics: In vitro and in vivo Studies.

Aloe vera is a plant with a long history of traditional medicinal use and is consumed in different products, sometimes in conjunction with prescribed medicines. A. vera gel has shown the ability to modulate drug absorption in vitro. The aim of this study was to fractionate the precipitated polysaccharide component of A. vera gel based on molecular weight and to compare their interactions with indinavir pharmacokinetics. Crude polysaccharides were precipitated from a solution of A. vera gel and was fractionated by means of centrifugal filtration through membranes with different molecular weight cut-off values (i.e. 300 KDa, 100 KDa and 30 KDa). Marker molecules were quantified in the aloe leaf materials by means of nuclear magnetic resonance spectroscopy and the average molecular weight was determined by means of gel filtration chromatography linked to multi-angle-laser-light scattering and refractive index detection. The effect of the aloe leaf materials on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers as well as indinavir metabolism in LS180 cells was measured. The bioavailability of indinavir in the presence and absence of the aloe leaf materials was determined in Sprague-Dawley rats. All the aloe leaf materials investigated in this study reduced the TEER of Caco-2 cell monolayers, inhibited indinavir metabolism in LS 180 cells to different extents and changed the bioavailability parameters of indinavir in rats compared to that of indinavir alone. These indinavir pharmacokinetic modulation effects were not dependent on the presence of aloverose and also not on the average molecular weight of the isolated fractions.

Novel protease inhibitor-loaded Nanoparticle-in-Microparticle Delivery System leads to a dramatic improvement of the oral pharmacokinetics in dogs.

With the advent of the Highly Active Antiretroviral Therapy, the morbidity and the mortality associated to HIV have been considerably reduced. However, 35-40 million people bear the infection worldwide. One of the main causes of therapeutic failure is the frequent administration of several antiretrovirals that results in low patient compliance and treatment cessation. In this work, we have developed an innovative Nanoparticle-in-Microparticle Delivery System (NiMDS) comprised of pure drug nanocrystals of the potent protease inhibitor indinavir free base (used as poorly water-soluble model protease inhibitor) produced by nanoprecipitation that were encapsulated within mucoadhesive polymeric microparticles. Pure drug nanoparticles and microparticles were thoroughly characterized by diverse complementary techniques. NiMDSs displayed an encapsulation efficiency of approximately 100% and a drug loading capacity of up to 43% w/w. In addition, mucoadhesiveness assays ex vivo conducted with bovine gut showed that film-coated microparticles were retained for more than 6 h. Finally, pharmacokinetics studies in mongrel dogs showed a dramatic 47- and 95-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the free unprocessed drug. These results support the outstanding performance of this platform to reduce the dose and the frequency of administration of protease inhibitors, a crucial step to overcome the current patient-incompliant therapy.

Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates.

HIV patients on combination oral drug therapy experience insufficient drug levels in lymph nodes, which is linked to viral persistence. Following success in enhancing lymph node drug levels and extending plasma residence time of indinavir formulated in lipid nanoparticles, we developed multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA). These anti-HIV LNPs were prepared, characterized, scaled up, and evaluated in primates with a focus on plasma time course and intracellular drug exposure in blood and lymph nodes. Four macaques were subcutaneously administered anti-HIV LNPs and free drug suspension in a crossover study. The time course of the plasma drug concentration as well as intracellular drug concentrations in blood and inguinal lymph nodes were analyzed to compare the effects of LNP formulation. Anti-HIV LNPs incorporated LPV and RTV with high efficiency and entrapped a reproducible fraction of hydrophilic PMPA. In primates, anti-HIV LNPs produced over 50-fold higher intracellular concentrations of LPV and RTV in lymph nodes compared to free drug. Plasma and intracellular drug levels in blood were enhanced and sustained up to 7 days, beyond that achievable by their free drug counterpart. Thus, multiple antiretroviral agents can be simultaneously incorporated into anti-HIV lipid nanoparticles to enhance intracellular drug concentrations in blood and lymph nodes, where viral replication persists. As these anti-HIV lipid nanoparticles also prolonged plasma drug exposure, they hold promise as a long-acting dosage form for HIV patients in addressing residual virus in cells and tissue.

Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine.

Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging. In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice. Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF. Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation. The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF. These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects. The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption.

Reduced indinavir exposure during pregnancy.

AIM: To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. METHODS: IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 µg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 µg ml(-1), the suggested minimum target. RESULTS: Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative. CONCLUSION: Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.

Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.

BACKGROUND: Combination drug therapy has reduced plasma HIV to undetectable levels; however, drug-sensitive virus persists in patients' lymphoid tissue. We have reported significant lymphoid tissue drug localization with indinavir-associated lipid nanoparticles (LNPs). Our current objective is to evaluate whether additional enhancement is achievable by targeting these particles to CD4-HIV host cells. METHODS: We characterized 2 peptide-coated (CD4-BP2 and CD4-BP4) drug-associated LNPs and demonstrated CD4-cell specificity. Drug-associated LNPs expressing polyethyleneglycol were exposed on HIV-2-infected cells under dynamic conditions that emulated lymph node physiology for 15, 30, and 60 minutes at concentrations from 0 to 25 µM and evaluated for antiviral activity and cell-associated drug concentrations. The specificity of CD4-mediated enhancement of indinavir LNPs antiviral activity was evaluated by blocking with anti-CD4 antibody. RESULTS: Inclusion of CD4-binding peptides on LNPs enhanced antiviral activity for all incubation conditions, compared with control particles or soluble drug (eg, 60 minutes exposure, EC50 = 0.12-0.13 vs. 0.46 µM for targeted nanoparticles vs. soluble drug). The CD4-BP4 peptide exhibited higher efficiency in eliciting antiviral activity than CD4-BP2-coated particles (EC50 = 7.5 µM vs. >25 µM at 15 minutes drug exposure). This enhancement seems to be driven by CD4 availability and cell-associated indinavir concentrations, as blocking of CD4 significantly ablated indinavir efficacy in targeted particles and indinavir concentrations reflected the observed anti-HIV activity. CONCLUSIONS: We constructed CD4-targeted LNPs that provide selective binding and efficient delivery of indinavir to CD4-HIV host cells. Inclusion of polyethyleneglycol in LNPs would minimize immune recognition of peptides. The enhancement of anti-HIV effects is effective even under limited time exposure.

Simultaneous quantitation of HIV-protease inhibitors ritonavir, lopinavir and indinavir in human plasma by UPLC-ESI-MS-MS.

A selective, sensitive and high-throughput ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method has been developed and validated for the quantification of HIV-protease inhibitors ritonavir (RTV), lopinavir (LPV) and indinavir (IDV) in human plasma. Sample clean-up involved protein precipitation of both drugs and fluconazole used as internal standard from 100 µL human plasma. All the analytes were chromatographically separated on a Waters Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 µm particle size) analytical column using 0.1% formic acid and methanol (40:60, v/v) as the mobile phase. The parent → product ion transitions for ritonavir (m/z 721.40→ 296.10), lopinavir (m/z 629.40→ 447.40) and indinavir (m/z 614.4→ 421.0) IS (m/z 307.10 → 220.10) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and positive ion mode. The method was validated over the concentration range of 30-15,000 ng/mL for LPV and IDV and 3-1500 ng/mL for RTV. The method was successfully applied to a pilot bioequivalence study in 36 healthy human subjects after oral administration of lopinavir 200 mg and ritonavir 50 mg tablet formulation under fasting conditions.

Impact of the herbal medicine Sophora flavescens on the oral pharmacokinetics of indinavir in rats: the involvement of CYP3A and P-glycoprotein.

Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%-83% decrease in AUC(0-∞) and 38%-78% reduction in C(max). The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products.

Pharmacokinetics and 48 week efficacy of adjusted dose indinavir/ritonavir in rifampicin-treated HIV/tuberculosis-coinfected patients: a pilot study.

HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/µl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure.

Lack of a pharmacokinetic drug-drug interaction with venlafaxine extended-release/indinavir and desvenlafaxine extended-release/indinavir.

PURPOSE: To assess the effects of venlafaxine extended-release (XR) capsules and desvenlafaxine extended-release (XR) tablets upon indinavir pharmacokinetic properties when co-administrated to healthy volunteers. METHODS: This was an open-label, two-period, fixed-dose study conducted at the clinical research unit located on a university campus. Twenty-four healthy volunteers enrolled in the study (mean age 28.3 ± 8.0 years). Each subject received a single dose of indinavir 800 mg on day 1. Subsequently, subjects were then randomly assigned to either the venlafaxine XR group (N = 12) or the desvenlafaxine XR group (N = 12). Starting on day 2, venlafaxine XR was dosed at 37.5 mg/day for 4 days and increased to 75 mg/day for 6 days. Desvenlafaxine XR was dosed at 50 mg/day for 10 days. On day 12, indivanvir 800 mg was co-administered to both the venlafaxine XR and the desvenlafaxine XR groups. The pharmacokinetics of indinavir were determined both before and at the end of antidepressant dosing. Plasma indinavir, venlafaxine, and desvenlafaxine concentrations were assayed by high-performance liquid chromatography with ultra-violet (UV) detection. Indinavir pharmacokinetic parameters were calculated by noncompartmental analysis using validated computer software. RESULTS: Venlafaxine XR and desvenlafaxine XR did not produce any significant changes in indinavir disposition. Both antidepressants were well tolerated by the subjects with only minor adverse side effects. CONCLUSIONS: No pharmacokinetic drug-drug interaction was demonstrated between venlafaxine XR and indinavir or between desvenlafaxine XR and indinvair. The lack of interaction could be due to the venlafaxine and desvenlafaxine extended-release formulation.

[Evidence-based therapeutic drug monitoring for indinavir]. / Niveau de preuve du suivi thérapeutique pharmacologique de l'indinavir.

The HIV protease inhibitor indinavir presents a wide inter-individual variability related to an intense hepatic metabolism. Published studies were analyzed to establish whether there is evidence that therapeutic drug monitoring of indinavir could improve patient care. It was reported that indinavir virological efficacy in HIV-infected patients with wild-type virus was significantly associated with trough concentrations > 100-150 ng/mL. Concerning the exposure-toxicity relationship, the risk of occurrence of nephrotoxicity was more frequently associated with trough concentrations > 500-1 000 ng/mL. Studies with concentration-controlled indinavir therapy suggest that therapeutic drug monitoring allows to achieve safe and effective concentrations, therefore, the level of evidence of the interest of indinavir therapeutic drug monitoring is highly recommended when indinavir is not associated with ritonavir and recommended when ritonavir is combined with ritonavir.