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ABSTRACT: Objectives: Raltegravir pharmacokinetics (PK) show high intra-and inter-patient variability and are also influ-enced by co-administered substances that alter the gastrointestinal tract environment, such as pH-altering or metal-containing agents. The aim of this investigation was to develop a population-based absorption, distribu-tion, metabolism and excretion (ADME) model to investigate the effects of gastrointestinal pH and ingested magnesium on raltegravir PK. Methods: In vitro data describing the disposition of raltegravir were obtained from literature sources or gener-ated by standard methods. Raltegravir (400 mg single dose) PK were simulated in healthy volunteers (50 sub-jects per group, 20 –50 years old, 0.5 proportion female subjects) over a 12 h period. Results: Simulated raltegravir PK correlated well with data from clinical trials, with a mean deviation in C max , AUC 0-12 and C trough of ,20%. Solubility of raltegravir in the gastrointestinal tract was increased at higher luminal pH. Increased intestinal pH and transit time both correlated with higher raltegravir absorption (P,0.001). Magnesium ingestion reduced raltegravir exposure in simulated subjects, with mean C trough reduced by 32% (P,0.001). Conclusions: The in vitro –in vivo extrapolation model developed in this study predicted raltegravir PK in virtual individuals with different gastrointestinal pH profiles. The main PK variables were predicted with good accuracy compared with reference data, and both luminal pH and magnesium were able to influence drug absorption. This modelling system provides a tool for investigating the absorption of other drugs, including HIV integrase inhibitors currently in development, which have also shown interactions with food and metal-containing products.
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ABSTRACT: OBJECTIVES: Raltegravir pharmacokinetics (PK) show high intra- and inter-patient variability and are also influenced by co-administered substances that alter the gastrointestinal tract environment, such as pH-altering or metal-containing agents. The aim of this investigation was to develop a population-based absorption, distribution, metabolism and excretion (ADME) model to investigate the effects of gastrointestinal pH and ingested magnesium on raltegravir PK. METHODS: In vitro data describing the disposition of raltegravir were obtained from literature sources or generated by standard methods. Raltegravir (400 mg single dose) PK were simulated in healthy volunteers (50 subjects per group, 20-50 years old, 0.5 proportion female subjects) over a 12 h period. RESULTS: Simulated raltegravir PK correlated well with data from clinical trials, with a mean deviation in Cmax, AUC0-12 and Ctrough of <20%. Solubility of raltegravir in the gastrointestinal tract was increased at higher luminal pH. Increased intestinal pH and transit time both correlated with higher raltegravir absorption (P < 0.001). Magnesium ingestion reduced raltegravir exposure in simulated subjects, with mean Ctrough reduced by 32% (P < 0.001). CONCLUSIONS: The in vitro-in vivo extrapolation model developed in this study predicted raltegravir PK in virtual individuals with different gastrointestinal pH profiles. The main PK variables were predicted with good accuracy compared with reference data, and both luminal pH and magnesium were able to influence drug absorption. This modelling system provides a tool for investigating the absorption of other drugs, including HIV integrase inhibitors currently in development, which have also shown interactions with food and metal-containing products.
Journal of Antimicrobial Chemotherapy 03/2013; · 5.07 Impact Factor
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ABSTRACT: BACKGROUND AND OBJECTIVE: The rate of depression in patients with HIV is higher than in the general population. The use of antidepressants can have a beneficial effect, improving antiretroviral therapy adherence and consequently their efficacy and safety. Efavirenz and protease inhibitor boosted with ritonavir are major components of the antiretroviral therapy and are inducers and/or inhibitors of several cytochrome P450 (CYP) isoforms. Although antidepressants are prescribed to a significant proportion of patients treated with antiretrovirals, there are limited clinical data on drug-drug interactions. The aim of this study was to predict the magnitude of drug-drug interactions among efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants using an in vitro-in vivo extrapolation (IVIVE) model simulating virtual clinical trials. METHODS: In vitro data describing the chemical characteristics, and absorption, distribution, metabolism and elimination (ADME) properties of efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants were obtained from published literature or generated by standard methods. Pharmacokinetics and drug-drug interaction were simulated using the full physiologically based pharmacokinetic model implemented in the Simcyp™ ADME simulator. The robustness of our modeling approach was assessed by comparing the magnitude of simulated drug-drug interactions using probe drugs to that observed in clinical studies. RESULTS: Simulated pharmacokinetics and drug-drug interactions were in concordance with available clinical data. Although the simulated drug-drug interactions with antidepressants were overall weak to moderate according to the classification of the US FDA, fluoxetine and venlafaxine represent better candidates from a pharmacokinetic standpoint for patients on efavirenz and venlafaxine or citalopram for patients on boosted protease inhibitors. CONCLUSION: The modest magnitude of interaction could be explained by the fact that antidepressants are substrates of multiple isoforms and thus metabolism can still occur through CYPs that are weakly impacted by efavirenz or boosted protease inhibitors. These findings indicate that IVIVE is a useful tool for predicting drug-drug interactions and designing prospective clinical trials, giving insight into the variability of exposure, sample size and time-dependent induction or inhibition.
Clinical Pharmacokinetics 03/2013; · 5.40 Impact Factor
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ABSTRACT: Purpose
To treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design.
Methods
In vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days.
Results
Simulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether Cmax by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether.
Conclusions
The model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition.
In Silico Pharmacology. 03/2013; 1(4).
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ABSTRACT: Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug-delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment.
Therapeutic delivery 02/2013; 4(2):153-6.
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Antonio D'Avolio,
Marco Simiele,
Andrea Calcagno, Marco Siccardi,
Giovanna Larovere,
Silvia Agati,
Lorena Baietto,
Jessica Cusato,
Mariacristina Tettoni,
Mauro Sciandra,
Laura Trentini,
Giovanni Di Perri,
Stefano Bonora
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ABSTRACT: OBJECTIVES: Ritonavir, used at low doses as a boosting agent of other protease inhibitors (PIs), is known to be associated with metabolic complications and gastrointestinal disturbances. The rate of accumulation of ritonavir within cells is still debated due to scarce data and methodological limitations. Therefore, our aim was to evaluate intracellular ritonavir penetration when used with different boosted PIs in the clinical setting. METHODS: Patients administered with atazanavir/ritonavir (300/100 mg, once daily), darunavir/ritonavir [600/100 mg, twice daily (darunavir-600) and 800/100 mg, once daily (darunavir-800)], lopinavir/ritonavir (400/100 mg, twice daily) and tipranavir/ritonavir (500/200 mg, twice daily) were considered. Blood sampling at the end of the dosing interval (C(trough)) was performed. Peripheral blood mononuclear cell (PBMC)-associated and plasma ritonavir and PI concentrations were measured by validated HPLC methods. PBMC count and individual mean cell volume (MCV) were measured using a Coulter Counter instrument. RESULTS: One hundred patients were enrolled. Frequencies of ritonavir-boosted PIs were atazanavir, 37%; darunavir-600, 23%; lopinavir, 19%; tipranavir, 13%; and darunavir-800, 8%. The median intracellular and plasma concentrations of ritonavir were 1279 ng/mL (IQR 727-2087) and 170 ng/mL (IQR 82-384), respectively, accounting for a cellular accumulation ratio of 7.69 (5.7-10.9). Significant differences in ritonavir intracellular concentrations emerged among different PIs (P < 0.001): specifically between darunavir-600 and atazanavir (P < 0.001), between darunavir-600 and tipranavir (P = 0.009), between atazanavir and lopinavir (P < 0.001) and between lopinavir and tipranavir (P = 0.027). CONCLUSIONS: Our study showed a higher rate of ritonavir intracellular accumulation than previously reported, possibly due to the more accurate calculation of intracellular concentrations by MCV. The ratio varied according to concomitantly administered PIs, suggesting their influence on the rate of ritonavir intracellular penetration.
Journal of Antimicrobial Chemotherapy 12/2012; · 5.07 Impact Factor
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Antonio Dʼavolio,
Alessia Ciancio, Marco Siccardi,
Antonina Smedile,
Marco Simiele,
Jessica Cusato,
Lorena Baietto,
Diego Aguilar Marucco,
Giuseppe Cariti,
Andrea Calcagno,
Daniel Gonzalez de Requena,
Mauro Sciandra,
Giulia Troshina,
Gian Paolo Caviglia,
Stefano Bonora,
Mario Rizzetto,
Giovanni Di Perri
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ABSTRACT: OBJECTIVES:: The response rate to treatment of chronic hepatitis C virus-genotype 1 and 4 infections was recently found to be strongly influenced by many polymorphisms. The aim of our study was to carry out an integrated analysis of the effects of polymorphisms and ribavirin (RBV) plasma exposure on outcome. METHODS:: The retrospective analysis included 174 patients. IL28B, CYP27B1, SLC29A1, SLC28A3, and SLC28A2 polymorphisms were genotyped and tested for association with sustained virological response. The impact of RBV plasma exposure during the first 3 months of therapy on outcome was also investigated. RESULTS:: Considering patients infected by hepatitis C virus-1/4, 3 polymorphisms (IL28B rs8099917TT, CYP27B1 rs4646536TT, and CNT2 rs11854484TT) were associated with sustained virological response. The number of negative variant allele and low RBV exposure were correlated to percentage increasing to therapy failure, suggesting some degree of cumulative effect of the 4 factors. A cutoff of 2.5 μg/mL of RBV was found to be associated with outcome (area under ROC [AUROC] curve = 0.64, sensitivity = 55.0%, and specificity = 71.2%, P = 0.020). In multivariate logistic regression analyses, each variant allele and RBV plasma exposure cutoff were independently associated with outcome. CONCLUSIONS:: In this study, we found that additional polymorphisms and RBV plasma exposure are also able to influence the achievement of response. Regardless of the magnitude of RBV pharmacokinetic exposure, the negative predictive value of the polymorphisms here investigated is much stronger than the positive one.
Therapeutic drug monitoring 12/2012; 34(6):722-728. · 2.43 Impact Factor
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Lorena Baietto,
Francesco G De Rosa,
Antonio Dʼavolio,
Cristina Marra,
Simone Pace,
Eleonora Biasin,
Francesca Carraro,
Francesca Nesi,
Marco Simiele,
Jessica Cusato, Marco Siccardi,
Giovanni Di Perri
Therapeutic drug monitoring 10/2012; 34(5):604-6. · 2.43 Impact Factor
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ABSTRACT: • Nevirapine pharmacokinetics are affected by several factors including CYP2B6 single nucleotide polymorphisms (SNPs). These genetic profiles are more common in African patients and they affect the drug clearance being associated with higher trough concentrations. Pharmacokinetic/pharmacogenetic (PK/PG) studies are difficult to perform in remote areas where refrigeration is not available, although dried plasma and dried blood methods have been validated.
• Dried plasma spots are useful tools for studying nevirapine PK with a good association to plasma concentrations and they can be used in rural areas since a cold chain is not necessary. Dried blood spots can be used to store and analyze patients' DNA for PG polymorphisms. Nevirapine trough concentrations in Burundese patients, not studied so far, are above the target concentration (3000 ng ml(-1) ) in 84% of patients. CYP2B6 (both at position 516 and 983) but not ABCB1 (3435 and 1236) SNPs as well as age correlate with higher nevirapine exposure.
The pharmacokinetics (PK) and pharmacogenetics (PG) of nevirapine have been studied in rich and limited-resource countries. CYP2B6 single nucleotide polymorphisms (SNPs) have been associated with decreased drug clearance. We evaluated the PG determinants of nevirapine trough concentrations in a rural cohort in Burundi using easy to store and transport dried sample spot devices.
A cross-sectional analysis in HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, was performed in 2009. After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature. Nevirapine plasma and dried sample spot concentrations were compared to test the clinical usefulness of this method. SNPs in CYP2B6 and ABCB1 (using a real time PCR technique) were analyzed and associated with nevirapine plasma trough concentrations.
Nevirapine concentrations measured on dried plasma spot devices were highly related to plasma concentrations in 60 patients, although a negative bias was observed (-18%). Nevirapine trough concentrations were above the target concentration (3000 ng ml(-1) ) in 84% of patients and they were associated with CYP2B6 SNPs (both at position 516 and 983). No effect of ABCB1 SNPs was noted.
Dried plasma spot devices are accurate tools for measuring nevirapine concentrations in rural settings where refrigeration is not available, despite a moderate underestimation bias. They allowed the evaluation of nevirapine concentrations in a cohort of HIV-infected people in rural Burundi, confirming very good exposure and correlation with PG polymorphisms in the CYP2B6 encoding gene.
British Journal of Clinical Pharmacology 07/2012; 74(1):134-40. · 2.96 Impact Factor
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ABSTRACT: To compare cerebrospinal fluid (CSF) darunavir and ritonavir concentrations in patients receiving darunavir/ritonavir 800/100 mg once daily or 600/100 mg twice daily. To determine the influence of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters (ABCB1 3435 C>T, ABCB1 1236 C>T, ABCB1 2677 G>T, SLCO1A2 38 A>G, SLCO1A2 516 A>C, ABCC2 -24 G>A) on darunavir and ritonavir penetration into CSF.
Comparative pharmacokinetics study in patients.
Plasma and CSF darunavir and ritonavir concentrations (2-26 h after drug intake) were determined by a validated HPLC coupled with mass spectrometry method in adults on darunavir-based combination antiretroviral therapy undergoing a lumbar puncture.
HIV-infected patients on once-daily darunavir/ritonavir had significantly lower CSF darunavir trough concentrations and CSF-to-plasma ratios than patients on darunavir/ritonavir twice-daily (10.7 versus 38.2 ng/ml and 0.32 versus 0.90%; P < 0.05). No significant effect of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters was noted apart from slightly higher CSF darunavir penetration in patients carrying OATP1A2 uncommon variants.
This is the first study to compare darunavir CSF concentrations in patients taking the once-daily or the twice-daily dosage: our data show that darunavir and ritonavir dosing significantly affects not only CSF concentrations but also the extent of drug penetration into the CSF. Furthermore a minority of patients in the once-daily arm presented very low CSF concentration of potential concern for HIV control in the central nervous system. The relative importance of pharmacogenetics in influencing CSF darunavir pharmacokinetics deserves further clinical investigation.
AIDS (London, England) 05/2012; 26(12):1529-33. · 4.91 Impact Factor
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ABSTRACT: A simultaneous extraction method to measure daptomycin, amikacin, gentamicin, and rifampicin in human plasma, by high-performance
liquid chromatography, was developed and validated. The method involved a rapid sample preparation by protein precipitation
with acetonitrile followed by direct injection into a high-performance liquid chromatography system coupled with mass detection.
Drug retention times were 10.00 ± 0.25, 2.00 ± 0.25, 3.50 ± 0.25, 11.50 ± 0.25, and 12.50 ± 0.25min for daptomycin, amikacin,
gentamicin, rifampicin, and quinoxaline, respectively. Good linearity (mean r
2 = 0.998) was obtained for all drugs quantified over the range of clinically relevant concentrations in human plasma and the
use of the internal standard quinoxaline improves accuracy (RSD% <14.9%) and intra-day (RSD% <11.56) and inter-day (RSD% <12.10)
precision for the analytical procedure. The limits of quantification for daptomycin, amikacin, gentamicin, and rifampicin
were 1.56, 2.34, 0.63, 0.63μg/ml, respectively. Moreover, the addition of ion pair trifluoroacetic acid in the sample allowed
the majority of gentamicin and amikacin separation. A rapid, specific, sensitive, accurate, and reproducible HPLC method was
developed and validated to measure daptomycin, amikacin, gentamicin, and rifampicin in human plasma. This method is suitable
for clinical pharmacokinetic studies.
Analytical and Bioanalytical Chemistry 04/2012; 396(2):791-798. · 3.78 Impact Factor
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ABSTRACT: Raltegravir shows marked pharmacokinetic variability in patients, with gastrointestinal pH and divalent-metal binding being potential factors. We investigated raltegravir solubility, lipophilicity, pK(a), and permeativity in vitro to elucidate known interactions with omeprazole, antacids, and food, all of which increase gastric pH. Solubility of raltegravir was determined at pH 1 to 8. Lipophilicity of raltegravir was determined using octanol-water partition. Raltegravir pK(a) was determined using UV spectroscopy. The effects of pH, metal salts, and omeprazole on the cellular permeativity of raltegravir were determined using Caco-2 monolayers. Cellular accumulation studies were used to determine the effect of interplay between pH and ABCB1 transport on raltegravir accumulation. Samples were analyzed using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) or scintillation counting. Raltegravir at 10 mM was partly insoluble at pH 6.6 and below. Raltegravir lipophilicity was pH dependent and was reduced as pH was increased from 5 to 9. The pK(a) of raltegravir was 6.7. Raltegravir cellular permeativity was heavily influenced by changes in extracellular pH, where apical-to-basolateral permeativity was reduced 9-fold (P < 0.05) when apical pH was increased from 5 to 8.5. Raltegravir cellular permeativity was also reduced in the presence of magnesium and calcium. Omeprazole did not alter raltegravir cellular permeativity. Cellular accumulation of raltegravir was increased independently by inhibiting ABCB1 and by lowering extracellular pH from pH 8 to 5. Gastrointestinal pH and polyvalent metals can potentially alter the pharmacokinetic properties of raltegravir, and these data provide an explanation for the variability in raltegravir exposure in patients. The evaluation of how divalent-metal-containing products, such as multivitamins, that do not affect gastric pH alter raltegravir pharmacokinetics in patients is now justified.
Antimicrobial Agents and Chemotherapy 03/2012; 56(6):3020-6. · 4.84 Impact Factor
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Marco Siccardi,
Antonio DʼAvolio,
Sonia Rodriguez-Novoa,
Lorena Cuenca,
Marco Simiele,
Lorena Baietto,
Andrea Calcagno,
Darren Moss,
Stefano Bonora,
Vicente Soriano,
David J Back,
Andrew Owen,
Giovanni Di Perri
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ABSTRACT: Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (Ctrough) in the clinical setting, the effect of UGT1A1*28 and concomitant antiretrovirals.
A total of 86 patients, from Turin, Italy, and Madrid, Spain, were included in the analysis. Blood samples were obtained 10-14 hours postdose. Genotyping for UGT1A1*28 was conducted by sequencing.
High interpatient and intrapatient variabilities were observed; 13 patients had ≥3 samples available, and the median coefficient of variation was 128 (64-265). Coadministration of RAL with atazanavir (ATV, n = 9) resulted in higher raltegravir Ctrough, 517 (307-2706) ng/mL when compared with patients not receiving ATV (n = 77) 223 (95-552; P = 0.02). UGT1A1*28 did not influence RAL plasma exposure.
We have documented large intersubject and intrasubject variabilities in RAL plasma concentrations and confirmed the interaction with ATV. Further studies are required to better understand the mechanisms that influence the pharmacokinetics of RAL.
Therapeutic drug monitoring 03/2012; 34(2):232-5. · 2.43 Impact Factor
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Antonio DʼAvolio,
Alessia Ciancio, Marco Siccardi,
Antonina Smedile,
Lorena Baietto,
Marco Simiele,
Diego Aguilar Marucco,
Giuseppe Cariti,
Andrea Calcagno,
Daniel Gonzalez de Requena,
Mauro Sciandra,
Jessica Cusato,
Giulia Troshina,
Stefano Bonora,
Mario Rizzetto,
Giovanni Di Perri
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ABSTRACT: Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors.
A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations.
Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 μg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 μg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4.
Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.
Therapeutic drug monitoring 03/2012; 34(2):165-70. · 2.43 Impact Factor
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Laura J Else,
Akil Jackson,
Rebekah Puls,
Andrew Hill,
Paul Fahey,
Enmoore Lin,
Alieu Amara, Marco Siccardi,
Victoria Watson,
John Tjia,
Sean Emery,
Saye Khoo,
David J Back,
Marta Boffito
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ABSTRACT: There is interest in evaluating the efficacy of lower doses of certain antiretrovirals for clinical care. We determined here the bioequivalence of plasma lamivudine (3TC) and intracellular 3TC-triphosphate (3TC-TP) concentrations after the administration of two different doses. ENCORE 2 was a randomized crossover study. Subjects received 3TC at 300 and 150 mg once daily for 10 days (arm 1; n = 13) or vice versa (arm 2; n = 11), separated by a 10-day washout. Pharmacokinetic (PK) profiles (0 to 24 h) were assessed on days 10 and 30. Plasma 3TC and 3TC-TP levels in peripheral blood mononuclear cells were quantified by high-performance liquid chromatography-tandem mass spectrometry. Within-subject changes in PK parameters (the area under the concentration-time curve from 0 to 24 h [AUC(0-24)], the trough concentration of drug in plasma at 24 h [C(24)], and the maximum concentration of drug in plasma [C(max)]) were evaluated by determining the geometric mean ratios (GMRs) adjusted for study arm, period, and intra-individual variation. Regimens were considered bioequivalent if the 90% confidence interval (90% CI) fell within the range of 0.8 to 1.25. A total of 24 subjects completed the study. The GM (90% CI) 3TC AUC(0-24)), expressed as ng·h/ml, for the 300- and 150-mg doses were 8,354 (7,609 to 9,172) and 4,773 (4,408 to 5,169), respectively. Bioequivalence in 3TC PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.57 (0.55 to 0.60), 0.63 (0.59 to 0.67), and 0.56 (0.53 to 0.60), respectively. The GM (90% CI) 3TC-TP AUC(0-24) values (pmol·h/10(6) cells) for the 300- and 150-mg doses were 59.5 (51.8 to 68.3) and 44.0 (38.0 to 51.0), respectively. Bioequivalence in 3TC-TP PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.73 (0.64 to 0.83), 0.82 (0.68 to 0.99), and 0.70 (0.61 to 0.82), respectively. We found that 3TC at 150 mg is not bioequivalent to the standard regimen of 300 mg, indicating that saturation of cytosine phosphorylation pathways is not achieved at a dose of 150 mg.
Antimicrobial Agents and Chemotherapy 12/2011; 56(3):1427-33. · 4.84 Impact Factor
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Chinyere Okoli, Marco Siccardi,
Sathish Thomas-William,
Ngozi Dufty,
Kirstin Khonyongwa,
Jonathan Ainsworth,
John Watson,
Roseanne Cook,
Kate Gandhi,
Geraldine Hickinbottom,
Andrew Owen,
Stephen Taylor
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ABSTRACT: To describe the pharmacokinetics of maraviroc when dosed at 150 or 300 mg once daily with 800/100 mg of darunavir/ritonavir.
A retrospective case-note review of HIV-infected adults taking maraviroc was conducted. Patients on a maraviroc-based regimen for a minimum of 5 weeks were grouped as receiving: (i) 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine; (ii) 300 mg of maraviroc once daily with 800/100 mg of darunavir/ritonavir once daily; and (iii) 150 mg of maraviroc once daily with 800/100 mg of darunavir/ritonavir once daily. C(trough) and C(peak) data were collected at 2, 12 or 24 h post-dose.
Sixty-six patients were included, providing 115 samples. The median (IQR) C(peak) was 378 (350-640) ng/mL for 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine (n=9), 728 (378-935) ng/mL for 300 mg of maraviroc once daily with darunavir/ritonavir (n=29) and 364 (104-624) ng/mL for 150 mg of maraviroc once daily with darunavir/ritonavir (n=2; P=0.24). The median (IQR) C(trough) was 46 (33-61) ng/mL for 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine (n=12), 70 (49-97) ng/mL for 300 mg of maraviroc once daily with darunavir/ritonavir (n=34) and 43 (35-55) ng/mL for 150 mg of maraviroc once daily with darunavir/ritonavir (n=17; P=0.001). The maraviroc C(trough) in black patients (n=34) was 61 (45-110) ng/mL and in white patients (n=29) it was 49 (42-70) ng/mL (P=0.04). The C(peak) in black patients (n=20) was 800 (397-1060) ng/mL versus 387 (336-723) ng/mL in white patients (n=20; P=0.02).
Once daily coadministration of 300 mg of maraviroc with 800/100 mg of darunavir/ritonavir was well tolerated and had favourable pharmacokinetics when compared with 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine. A 24% higher C(trough) and 107% higher C(peak) was seen in black patients compared with white patients.
Journal of Antimicrobial Chemotherapy 12/2011; 67(3):671-4. · 5.07 Impact Factor
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Neill J Liptrott,
Sudeep Pushpakom,
Christoph Wyen,
Gerd Fätkenheuer,
Christian Hoffmann,
Stefan Mauss,
Heribert Knechten,
Norbert H Brockmeyer,
Elizabeth Hopper-Borge, Marco Siccardi,
David J Back,
Saye H Khoo,
Munir Pirmohamed,
Andrew Owen
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ABSTRACT: Nevirapine exhibits marked interpatient variability in pharmacokinetics. CYP2B6 activity and demographic factors are important, but there are a few data on drug transporters for nevirapine. ABCC10 (MRP7) is an efflux transporter highly expressed in liver, intestine, and peripheral blood cells. We investigated whether nevirapine is a substrate for ABCC10 and whether genetic variants contribute to variability in nevirapine plasma concentrations.
Accumulation of nevirapine was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4+ cells, and monocyte-derived macrophages from healthy volunteers (n=8). ABCC10 small interfering RNA studies were also conducted. DNA samples with paired plasma drug concentrations were available from 163 HIV-infected patients receiving nevirapine-containing regimens. Sequenom was used to screen 14 single nucleotide polymorphisms in ABCC10. Linear regression models were used to identify factors independently associated with nevirapine plasma concentration.
Nevirapine accumulation was 37% lower in HEK293-ABCC10 cells compared with parental HEK293 cells (P=0.02), and this was reversed by cepharanthine (an ABCC10 inhibitor). After small interfering RNA knockdown of ABCC10, there was an increase in accumulation of nevirapine in CD4 cells (32%; P=0.03) and monocyte-derived macrophages (38%; P=0.04). Marked differences in the haplotype structure of ABCC10 was observed between White and Black patients in the cohort. In Whites, an exonic single nucleotide polymorphism (rs2125739) was significantly associated with nevirapine plasma concentration (P=0.02). Multivariate regression analysis identified carriage of a composite genotype of ABCC10 rs2125739 and CYP2B6 516G>T (P=0.001), time post dose (P=0.01) and BMI (P=0.07) to be independently associated with nevirapine plasma concentrations.
Nevirapine is a substrate for ABCC10 and genetic variants influence its plasma concentrations. ABCC10 in lymphocytes and macrophages may also contribute to variability in intracellular permeation of nevirapine. Further studies are required to determine the clinical implications of these findings.
Pharmacogenetics and Genomics 11/2011; 22(1):10-9. · 3.48 Impact Factor
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Antonio D'Avolio,
Alessia Ciancio, Marco Siccardi,
Lorena Baietto,
Marco Simiele,
Giuseppe Cariti,
Andrea Calcagno,
Antonina Smedile,
Jessica Cusato,
Stefano Bonora,
Mario Rizzetto,
Giovanni Di Perri
Hepatology 09/2011; 54(6):2278-9. · 11.66 Impact Factor
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Christoph Wyen,
Heidy Hendra, Marco Siccardi,
Martin Platten,
Hans Jaeger,
Thomas Harrer,
Stefan Esser,
Johannes R Bogner,
Norbert H Brockmeyer,
Bernhard Bieniek, [......],
Claudia Michalik,
Verena Dlugay,
Alexander Jetter,
Heribert Knechten,
Hartwig Klinker,
Adriane Skaletz-Rorowski,
Gerd Fätkenheuer,
Deirdre Egan,
David J Back,
Andrew Owen
[show abstract]
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ABSTRACT: Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy.
Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation.
Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months.
These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.
Journal of Antimicrobial Chemotherapy 06/2011; 66(9):2092-8. · 5.07 Impact Factor
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Silvia Garazzino,
Alessandro Aprato,
Lorena Baietto,
Antonio D'Avolio,
Agostino Maiello,
Francesco Giuseppe De Rosa,
Domenico Aloj, Marco Siccardi,
Antonio Biasibetti,
Alessandro Massè,
Giovanni Di Perri
[show abstract]
[hide abstract]
ABSTRACT: A main determinant of clinical response to antibiotic treatment is drug concentration at the infected site. Data on ceftriaxone (CFX) bone penetration are lacking. We measured CFX concentrations in infected bone to verify their relationship with pharmacodynamic microbiological markers.
Eleven patients undergoing debridement for septic non-union of the tibia and receiving intravenous CFX were studied. Plasma and bone specimens were collected intraoperatively at a variable interval after CFX administration. Drug concentrations were measured by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method.
Bone samples were extracted at a mean of 3.3 h (range 1.5-8.0 h) since the start of CFX infusion. The mean±standard deviation intraoperative CFX plasma concentration was 128.4±30.8 mg/l; the corresponding bone concentrations were 9.6±3.4 mg/l (7.8%) in the cortical compartment and 30.8±8.6 mg/l (24.3%) in the cancellous compartment. The mean 24-h area under the concentration-time curve (AUC(24)) values were 176.8±62.2 h*mg/l in cortical bone and 461.5±106.8 h*mg/l in cancellous bone. The time above the minimum inhibitory concentration (T>MIC) was 24 h in all compartments. The estimated mean free AUC/MIC ratios and T>MIC were 140 and 24.4 h, respectively, in cancellous bone and 42.4 and 21 h, respectively, in cortical bone.
CFX bone penetration was poor (<15%) in the cortical compartment and satisfactory in the more vascularized cancellous bone. The T>MIC and AUC/MIC ratios suggest that CFX achieves a satisfactory pharmacokinetic exposure in cancellous bone as far as pathogens with a MIC of <0.5 are concerned. However, considering free drug concentrations, pharmacokinetic/pharmacodynamic targets may not be fully achieved in cortical bone. As antibiotic exposure can be suboptimal in the infected cortical compartment, and drug penetration may be impaired into necrotic bone and sequesters, a radical surgical removal of purulent and necrotic tissues appears essential to shorten treatment duration and to prevent treatment failures.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 06/2011; 15(6):e415-21. · 2.17 Impact Factor
