Publications
61 results found
Sousa M, Pozniak A, Boffito M, 2008, Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs., J Antimicrob Chemother, Vol: 62, Pages: 872-878
Malaria and tuberculosis (TB) are two major global diseases mostly affecting the developing countries. Their treatment is often complex because of the drugs used, multidrug resistance, drug interactions and logistic problems such as drug availability and access. Patients are treated for TB for a minimum of 6 months and may concomitantly develop and be treated for malaria, especially during the rainy season. Rifampicin, a standard component of combination regimens for treating TB, is a potent inducer of hepatic cytochrome and other metabolic enzymes and is able to influence the pharmacokinetics of many drugs. Rifabutin, another rifamycin used less frequently than rifampicin, can also interact with drugs metabolized through the hepatic cytochromes. The mechanisms of any interaction of rifamycins with drugs used in malaria are not well defined. To complicate matters, acute malaria also plays a role in the pharmacokinetics and pharmacodynamics of drugs (i.e. quinine). The aim of this paper is to review known and potential drug-drug interactions between rifampicin, rifabutin and antimalarial drugs.
Gazzard BG, Anderson J, Babiker A, et al., 2008, British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008., HIV Med, Vol: 9, Pages: 563-608
Singh K, Dickinson L, Chaikan A, et al., 2008, Pharmacokinetics and safety of saquinavir/ritonavir and omeprazole in HIV-infected subjects., Clin Pharmacol Ther, Vol: 83, Pages: 867-872
We investigated the pharmacokinetics and safety of saquinavir/ritonavir when administered with omeprazole simultaneously and 2 h apart to human immunodeficiency virus (HIV) subjects. Saquinavir/ritonavir 12-h pharmacokinetics was assessed with and without omeprazole 40 mg. Subjects were randomized to group A (saquinavir/ritonavir and omeprazole simultaneously/2 h apart) or group B (saquinavir/ritonavir and omeprazole 2 h apart/simultaneously). Saquinavir/ritonavir pharmacokinetics was assessed on days 1, 8, and 22. Within-subject changes were evaluated by geometric mean ratios and 90% confidence interval (CI). Twelve subjects completed the study. GM (90% CI) for saquinavir area under the curve (AUC)(0-12) (ng h/ml), trough concentration (C(trough)) (ng/ml), and maximum concentration (C(max)) (ng/ml) were 14,698 (13,242-20,636), 433 (368-758), 2,513 (2,243-3,329) without omeprazole; 22,646 (18,536-131,861), 750 (619-1,280), 3,890 (3,223-5,133) with omeprazole simultaneously; and 24,549 (20,884-38,894), 851 (720-1,782), 4,141 (3,554-5,992) with omeprazole 2 h earlier. Simultaneous administration of omeprazole significantly increased saquinavir AUC(0-12), C(trough), and C(max) by 54, 73, and 55%, whereas staggered administration by 67, 97, and 65%. No grade 3/4 toxicity or lab abnormalities were observed. In the presence of omeprazole, saquinavir plasma exposure is significantly increased in HIV-infected subjects whether administered simultaneously or 2 h apart.
Pozniak AL, Boffito M, Russell D, et al., 2008, A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 65, Pages: 54-59, ISSN: 0306-5251
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- Citations: 23
Boffito M, Miralles D, Hill A, 2008, Pharmacokinetics, efficacy, and safety of darunavir/ritonavir 800/100 mg once-daily in treatment-naïve and -experienced patients., HIV Clin Trials, Vol: 9, Pages: 418-427, ISSN: 1528-4336
Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The currently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a control arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration levels remained above the predefined EC(50) of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily [DOSAGE ERROR CORRECTED] were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir supports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resistance to darunavir.
Boffito M, Else L, Back D, et al., 2008, Pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug cessation., Antivir Ther, Vol: 13, Pages: 901-907, ISSN: 1359-6535
BACKGROUND: We investigated the pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug intake cessation. METHODS: This was an open-label, three-session, pharmacokinetic trial. Healthy volunteers received atazanavir/ritonavir 300/100 mg once daily and lopinavir/ritonavir 400/100 mg twice daily and 800/200 mg once daily separately for 10 days. Pharmacokinetic profiles were assessed for each phase on day 10 over 72 h. Pharmacokinetic parameters were determined over 12 or 24 h and to the last measurable concentration by non-compartmental methods. RESULTS: Sixteen participants completed the study. Geometric mean terminal elimination half-life to 72 h of atazanavir was 8.35 h and not different from the 0-24 h half-life (9.91 h). Terminal elimination halflife of lopinavir was 2.33 h (twice daily) and 2.44 h (once daily). These values were lower compared with the half-life over the respective dosing intervals (7.15 and 4.88 h for 0-12 and 0-24 h, respectively). No participant on atazanavir had concentrations below the minimum effective concentration (MEC) of 150 ng/ml at 24 h. In total, 44% of the participants on lopinavir once daily had concentrations below the MEC of 1,000 ng/ml at 24 h. At 16 h and 20 h, 13% and 63% of participants were below target for twice daily lopinavir, respectively. At 36 h, all participants on lopinavir and 31% on atazanavir were below target. Ritonavir area under the plasma concentration-time curve was 30% lower and 26% higher when dosed at 100 mg or 200 mg with lopinavir versus atazanavir. CONCLUSIONS: This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Whereas the decline in lopinavir concentrations occured rapidly as the boosting effect of ritonavir diminished, the rate of decline of atazanavir remained constant to 72 h.
De Lorenzo F, Collot-Teixeira S, Boffito M, et al., 2008, Metabolic-inflammatory changes, and accelerated atherosclerosis in HIV patients: rationale for preventative measures., Curr Med Chem, Vol: 15, Pages: 2991-2999, ISSN: 0929-8673
Human immunodeficiency virus (HIV)-infected patients are at a significantly higher risk from coronary heart diseases (CHD) and myocardial infarction (MI) compared to gender- and age-matched non-infected individuals. Combination antiretroviral therapy (cART) has transformed a fatal illness into a chronic stable condition. However, cART induces metabolic abnormalities in HIV-infected patients, while its role in vascular atherosclerosis is still under investigation. The use of cART is linked to inflammation - a key mechanism in atherosclerotic progression and destabilisation that precedes clinical events like MI. There is evidence of visceral fat abnormal distribution in HIV infected patients, and inflammatory changes in HIV infected patients drive the initiation, progression and, ultimately, thrombotic clinical complications induced by atherosclerosis. Visceral adipose tissue, a virtual factory for manufacturing pro-inflammatory mediators, affects the liver function. The inflamed liver promotes the development of pro-atherogenic dyslipidaemia. Pro-inflammatory cytokines released by adipocytes travel to the skeletal muscles and other peripheral tissues, worsening insulin sensitivity and leading to hyperglycaemia. Increased high sensitivity C-reactive protein (hs-CRP) inflammatory marker is associated with endothelial dysfunction in HIV-infected patients. Increased levels of monocytic nuclear factor kappa-B (NFkappa-B), a master switch in the inflammatory cascade, are documented in patients with elevated hs-CRP levels. It can be assumed that, as a result of NFkappa-B activation, hs-CRP up-regulates cytokines that contribute to MI by recruiting leukocytes and promoting thrombosis. This review focuses on the association of HIV-infection, metabolic abnormalities and known mechanisms involved in inducing accelerated atherosclerosis and inflammation in HIV-infected patients, as well as the role of lipid lowering agents in potentially preventing CHD.
Boffito M, Winston A, Jackson A, et al., 2007, Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance, AIDS, Vol: 21, Pages: 1449-1455, ISSN: 0269-9370
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- Citations: 62
Boffito M, 2007, Pharmacokinetics and pharmacodynamics in HAART and antibiotic therapy., New Microbiol, Vol: 30, Pages: 346-349, ISSN: 1121-7138
Therapeutic agents used to inhibit the HIV replication are used in combination. The achievement of effective plasma concentrations of the drug in its active form, and sustaining such concentrations for the duration of a dosing interval without exceeding thresholds of toxicity is fundamental in HIV therapy. The issues determining the absorption, biotransformation, distribution to and activity at the intended site, and elimination, are myriad and complex. Studies at molecular, cell, and tissue levels are useful for predicting the possible fate of these agents in vivo, but the wide inter individual variability shown in whole-body pharmacokinetic studies is illustrative of the difficulty in making general statements rather than more guarded recommendations.
Waters LJ, Moyle G, Bonora S, et al., 2007, Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients., Antivir Ther, Vol: 12, Pages: 825-830, ISSN: 1359-6535
BACKGROUND: Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals. METHODS: HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI). RESULTS: Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml. CONCLUSIONS: No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.
Gazzard B, Bernard AJ, Boffito M, et al., 2006, British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006)., HIV Med, Vol: 7, Pages: 487-503, ISSN: 1464-2662
Ford J, Boffito M, Maitland D, et al., 2006, Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients., J Antimicrob Chemother, Vol: 58, Pages: 1009-1016, ISSN: 0305-7453
OBJECTIVES: To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients. METHODS: Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined. RESULTS: In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02). CONCLUSIONS: The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir.
Boffito M, Pillay D, Wilkins E, 2006, Management of advanced HIV disease: resistance, antiretroviral brain penetration and malignancies., Int J Clin Pract, Vol: 60, Pages: 1098-1106, ISSN: 1368-5031
Data from Italy, Spain and the USA all highlight the worrying fact that presentation with advanced HIV disease - defined as a cluster of differentiation 4 (CD4) count <50 cells/mm(3) or the presence of an acquired immunodeficiency syndrome-defining illness - is increasingly common. A review from 2003 showed that 31% of patients in the UK and Ireland presented late (<200 CD4 cells/mm(3)). Early diagnosis is vital to ensure that patients benefit from antiretroviral therapy, and when patients present late, they do not obtain the benefits of early treatment. The risk of death is lower when antiretroviral therapy is initiated at CD4 counts of 201-350 cells/mm(3) than at lower CD4 cell counts. In addition, the risk of unintentional infection of others is increased, which is particularly troubling in light of evidence that transmission of resistance can occur even in the absence of antiretroviral therapy. The management of patients with advanced disease and no complications is complex, but issues of transmitted resistance and comorbid conditions further confuse management decisions in the treatment of patients with higher CD4 counts. This article reviews recent evidence on transmitted resistance, the pharmacokinetics of antiretroviral drugs in patients with central nervous system disease and the management issues in patients with comorbid malignancies to offer practical advice on therapeutic options for treatment-naïve patients who present with advanced HIV disease.
Winston A, Back D, Fletcher C, et al., 2006, Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers, AIDS, Vol: 20, Pages: 1401-1406, ISSN: 0269-9370
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- Citations: 33
Winston A, Mallon PWG, Boffito M, 2006, The clinical pharmacology of antiretrovirals in development, EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, Vol: 2, Pages: 447-458, ISSN: 1742-5255
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- Citations: 4
Fox J, Boffito M, Winston A, 2006, The clinical implications of antiretroviral pharmacogenomics, PHARMACOGENOMICS, Vol: 7, Pages: 587-596, ISSN: 1462-2416
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- Citations: 13
Boffito M, Pozniak A, Kearney BP, et al., 2005, Lack of pharmacokinetic drug interaction between tenofovir disoproxil fumarate and nelfinavir mesylate., Antimicrob Agents Chemother, Vol: 49, Pages: 4386-4389, ISSN: 0066-4804
A study explored the pharmacokinetics of tenofovir (300 mg administered once daily) and nelfinavir (1,250 mg twice daily) when coadministered in 29 healthy volunteers. Tenofovir, nelfinavir, and M8 pharmacokinetics was unaltered when tenofovir and nelfinavir were coadministered, and tenofovir administration did not affect the M8/nelfinavir area under the concentration-versus-time curve over the dosing interval (AUC(tau)) ratio. No interaction between tenofovir and nelfinavir was observed.
Maitland D, Moyle G, Hand J, et al., 2005, Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial., AIDS, Vol: 19, Pages: 1183-1188, ISSN: 0269-9370
OBJECTIVE: To compare the safety and efficacy of two once-daily antiretroviral regimens containing lamivudine (3TC) or tenofovir disoproxil fumarate (TDF), each administered with didanosine (ddI) and efavirenz (EFV) as initial therapy to HIV-1-infected subjects. METHODS: Single centre, randomized (1: 1), open-label study in antiretroviral-naive, HIV-infected adults. Subjects commenced either 3TC/ddI/EFV (3TC group) or TDF/ddI/EFV (TDF group). Safety, Medication Event Monitoring System (MEMScap) and plasma EFV concentration monitoring was performed over the study period. Comparisons between groups were assessed using chi test and linear regression analysis was used to assess the relationship between EFV concentrations and virological response. RESULTS: Seventy-seven subjects were enrolled prior to recruitment being suspended, 36 to the 3TC group and 41 to the TDF group. Intention-to-treat analysis in which last observation carried forward (LOCF) found the mean viral log10 load [95% confidence interval (CI)] at weeks 4 and 12 to be 2.67 (2.47-2.87) and 1.83 (1.74-1.92) for the 3TC group and 2.75 (2.45-3.05) and 2.28 (1.96-2.6) for the TDF group (P = 0.013). Emergence of resistance occurred in five of 41 (12.2%) subjects in the TDF group up to week 12 compared with none of 36 in the 3TC group, (P < 0.05); these five subjects shared similar baseline characteristics (CD4+ cell counts < 200 x 10 cells/l and HIV-1 RNA > 100,000 copies/ml). Despite MEMScap monitoring showing > 99% adherence in all subjects, among the five failures, three had low EFV concentrations. CONCLUSION: TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 x 10 cells/l and viral load > 100,000 copies/ml. Treatment failure with resistance was not attributable to baseline resistance, efavirenz exposure or poor adherence.
Winston A, Boffito M, 2005, The management of HIV-1 protease inhibitor pharmacokinetic interactions, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 56, Pages: 1-5, ISSN: 0305-7453
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- Citations: 37
Boffito M, Maitland D, Dickinson L, et al., 2005, Boosted saquinavir hard gel formulation exposure in HIV-infected subjects: ritonavir 100 mg once daily versus twice daily., J Antimicrob Chemother, Vol: 55, Pages: 542-545, ISSN: 0305-7453
OBJECTIVES: The amount of ritonavir needed to enhance saquinavir hard gel (hg) plasma concentrations is unclear. Reduced ritonavir dosing may help to reduce ritonavir-related side effects and costs. This study examined the pharmacokinetics of twice-daily saquinavir-hg (1000 mg) in the presence of ritonavir 100 mg, dosed twice-daily and once-daily on one single occasion. METHODS: Eighteen HIV-infected adults taking saquinavir/ritonavir 1000/100 mg twice-daily underwent pharmacokinetic (PK) assessment of saquinavir/ritonavir on day 1 following a morning saquinavir/ritonavir dose. On day 2, PK assessment was repeated when subjects took saquinavir without ritonavir. Drug intake (with a standard meal containing 20 g of fat) was timed on days -1, 1 and 2. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were calculated to assess changes in saquinavir PK parameters. RESULTS: Geometric mean saquinavir AUC(0-12), C(trough), C(max) and elimination half-life on days 1 and 2 were 14 389 and 9590 ng.h/mL, 331 and 234 ng/mL, 2503 and 1893 ng/mL and 2.80 and 2.82 h, respectively. The GMR (95% CI) for these parameters were 0.67 (0.53-0.84), 0.71 (0.48-1.04), 0.76 (0.58-0.98) and 1.01 (0.86-1.18), respectively. CONCLUSIONS: Withholding a ritonavir dose significantly reduces overall saquinavir exposure and C(max), but had no impact on the elimination half-life. These data establish the need to administer saquinavir and ritonavir simultaneously.
Boffito M, Maitland D, Samarasinghe Y, et al., 2005, The pharmacokinetics of HIV protease inhibitor combinations., Curr Opin Infect Dis, Vol: 18, Pages: 1-7, ISSN: 0951-7375
PURPOSE OF REVIEW: The clinical use of double-boosted protease inhibitor regimens has evolved recently. This strategy offers a number of unique benefits, including pharmacokinetic enhancement of two different protease inhibitors with low dose ritonavir. We review the pharmacologic rationale for the double-boosted protease inhibitor combinations and the complex drug-drug interactions that occur among different protease inhibitors when co-administered. RECENT FINDINGS: The discovery and widespread clinical use of low dose ritonavir as a pharmacoenhancer of other protease inhibitors has significantly improved the management of HIV infection treatment. This has subsequently led to the development of double-boosted protease inhibitor regimens which have been shown to be effective in heavily pre-treated patients, in whom it is crucial to maintain drug concentrations sufficient to suppress viruses with multiple resistance mutations. Interesting pharmacokinetic data have been recently produced showing the complexity of the interactions among three protease inhibitors. As the outcome of these multidrug interactions may be difficult to predict, formal pharmacokinetic studies have been fundamental to determine which protease inhibitors are best to administer in combination. SUMMARY: This review summarizes the current literature regarding the pharmacokinetics of double-boosted protease inhibitor regimens and general considerations regarding their usage in the treatment of HIV-infected patients.
Boffito M, Back D, Stainsby-Tron M, et al., 2005, Pharmacokinetics of saquinavir hard gel/ritonavir (1000/100 mg twice daily) when administered with tenofovir diproxil fumarate in HIV-1-infected subjects., Br J Clin Pharmacol, Vol: 59, Pages: 38-42, ISSN: 0306-5251
AIMS: To investigate whether the administration of tenofovir diproxil fumarate 300 mg once daily alters the plasma pharmacokinetics of the saquinavir hard gel/ritonavir combination in HIV-1 infected individuals. METHODS: On day 1, 12 h pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg given twice daily) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Tenofovir diproxil fumarate 300 mg given once daily was then added to the regimen and blood sampling was repeated at days 3 and 14. Saquinavir and ritonavir concentrations were measured by HPLC-MS/MS, and tenofovir concentrations by HPLC with UV detection. RESULTS: Following the addition of tenofovir diproxil fumarate to the regimen, saquinavir and ritonavir plasma concentrations were not significantly different compared with day 1. Thus the geometric mean ratios (95% confidence intervals) for the area under the concentration-time curve were 1.16 (0.97, 1.59) and 0.99 (0.87, 1.30) for saquinavir and 1.05 (0.92, 1.28) and 1.08 (0.97, 1.30) for ritonavir, on days 3 and 14, respectively. CONCLUSIONS: Tenofovir diproxil fumarate did not alter the pharmacokinetics of saquinavir hard gel/ritonavir.
Boffito M, Acosta E, Burger D, et al., 2005, Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs., Antivir Ther, Vol: 10, Pages: 469-477, ISSN: 1359-6535
The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met for the second time in Rome, Italy. This was following the inaugural meeting in Perugia, Italy, in October 2000, which resulted in the manuscript published in AIDS 2002, 16(Suppl 1):S5-S37. The objectives of this second meeting were to review and update the numerous questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. A major focus of the meeting was to discuss and critically analyse recent and precedent clinical drug-drug interaction data to provide a clear framework of the pharmacological basis of how one drug may impact the disposition of another. This report, which has been updated to include material published or presented at international conferences up to the end of December 2004, reviews recent pivotal pharmacokinetic interaction data and provides advice to clinical care providers on how some drug-drug interactions may be prevented, avoided or managed, and, when data are available, on what dose adjustments and interventions should be performed.
Boffito M, Acosta E, Burger D, et al., 2005, Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy., Antivir Ther, Vol: 10, Pages: 375-392, ISSN: 1359-6535
The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5-S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials.
Boffito M, Dickinson L, Hill A, et al., 2004, Steady-State pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients., J Acquir Immune Defic Syndr, Vol: 37, Pages: 1376-1384, ISSN: 1525-4135
BACKGROUND: In vitro synergy and complementary resistance profiles provide a strong rationale for combining fosamprenavir with saquinavir as part of a potent double-boosted protease inhibitor regimen. This study evaluated the steady-state pharmacokinetics of saquinavir 1000 mg twice daily (bid) and fosamprenavir 700 mg bid administered with 2 different doses of ritonavir (100 and 200 mg bid) in HIV-1-infected subjects. METHODS: On day 1, 12-hour pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg bid) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Fosamprenavir 700 mg bid was then added to the regimen, and pharmacokinetic sampling was repeated for all 3 agents at day 11. The ritonavir daily dose was then increased to 200 mg bid, and a 3rd pharmacokinetic profile was obtained at day 22. RESULTS: The coadministration of fosamprenavir 700 mg bid with saquinavir/ritonavir 1000/100 mg bid resulted in a statistically nonsignificant decrease in saquinavir concentrations (by 14, 9, and 24%, for saquinavir area under the concentration-time curve [AUC]0-12, C(max), and C(trough), respectively). This was compensated for by an increased ritonavir dose of 200 mg bid, which resulted in a statistically nonsignificant increase in saquinavir exposure compared with baseline. Amprenavir levels did not appear to be significantly influenced by coadministration of saquinavir with fosamprenavir. Fosamprenavir significantly reduced ritonavir exposure, but the increased ritonavir dose compensated for this interaction. CONCLUSIONS: Our findings showed that saquinavir/ritonavir/fosamprenavir was well tolerated over the study period. Saquinavir plasma concentrations were slightly lowered by the addition of fosamprenavir to the regimen. However, the addition of a further 100 mg ritonavir bid restored the small and insignificant decrease.
Samarasinghe YP, Boffito M, Di Perri G, 2004, Nucleoside/nucleotide reverse transcriptase inhibitor drug interactions., J HIV Ther, Vol: 9, Pages: 79-86, ISSN: 1462-0308
Since their advent the nucleoside and nucleotide reverse transcriptase inhibitors have consolidated their position as the 'backbone' of many antiretroviral therapy regimens. The ability of this class of drugs to combine successfully with members of their own as well as other antiretroviral classes has enabled the effective suppression of HIV replication to occur. Many of these therapeutic combinations rely on synergistic interactions to achieve this. There are, however, also many unfavourable pharmacokinetic and pharmacodynamic interactions between the members of nucleoside/nucleotide reverse transcriptase inhibitors, as well as with other antiretroviral classes and non-HIV drugs. This article aims to identify clinically relevant, beneficial and detrimental interactions of this class of antiretroviral agent.
Jackson A, Taylor S, Boffito M, 2004, Pharmacokinetics and pharmacodynamics of drug interactions involving HIV-1 protease inhibitors, AIDS REVIEWS, Vol: 6, Pages: 208-217, ISSN: 1139-6121
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- Citations: 9
Moyle G, Boffito M, 2004, Unexpected drug interactions and adverse events with antiretroviral drugs., Lancet, Vol: 364, Pages: 8-10
Boffito M, Kurowski M, Kruse G, et al., 2004, Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen, AIDS, Vol: 18, Pages: 1291-1297, ISSN: 0269-9370
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- Citations: 62
Boffito M, Dickinson L, Hill A, et al., 2004, Pharmacokinetics of once-daily saquinavir/ritonavir in HIV-infected subjects: comparison with the standard twice-daily regimen., Antivir Ther, Vol: 9, Pages: 423-429, ISSN: 1359-6535
OBJECTIVE: To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients. METHODS: Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model. RESULTS: Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656-2850) ng/ml for 1000 mg, 2782 (2249-4330) ng/ml for 1600 mg and 4179 (3429-6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453-1011), 106 (76-223) and 231 (75-822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients. CONCLUSION: This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerab
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