Pharmacokinetics and Pharmacodynamics of Once-Daily versus Twice-Daily Raltegravir in Treatment-Naïve HIV-Infected Patients

ABSTRACTQDMRK was a phase III clinical trial of raltegravir given once daily (QD) (800-mg dose) versus twice daily (BID) (400 mg per dose), each in combination with once-daily coformulated tenofovir-emtricitabine, in treatment-naive HIV-infected patients. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses were conducted using a 2-step approach: individual non-model-based PK parameters from observed sparse concentration data were determined, followed by statistical analysis of potential relationships between PK and efficacy response parameters after 48 weeks of treatment. Sparse PK sampling was performed for all patients (QD,n= 380; BID,n= 384); selected sites performed an intensive PK evaluation at week 4 (QD,n= 22; BID,n= 20). In the intensive PK subgroup, daily exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were similar between the two regimens, but patients on 800 mg QD experienced ∼4-fold-higher maximum drug concentration in plasma (Cmax) values and ∼6-fold-lower trough drug concentration (Ctrough) values than those on 400 mg BID. Geometric mean (GM)Ctroughvalues were similarly lower in the sparse PK analysis. With BID dosing, there was no indication of any significant PK/PD association over the range of tested PK parameters. With QD dosing,Ctroughvalues correlated with the likelihood of virologic response. Failure to achieve an HIV RNA level of <50 copies/ml appeared predominantly at high baseline HIV RNA levels in both treatment arms and was associated with lower values of GMCtroughin the 800-mg-QD arm, though other possible drivers of efficacy, such as time above a threshold concentration, could not be evaluated due to the sparse sampling scheme. Together, these findings emphasize the importance of the shape of the plasma concentration-versus-time curve for long-term efficacy.

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Pharmacokinetics of and Short-Term Virologic Response to Low-Dose 400-Milligram Once-Daily Raltegravir Maintenance Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05694-11 ◽

2012 ◽

Vol 56 (4) ◽

pp. 1892-1898 ◽

Cited By ~ 11

Author(s):

Jintanat Ananworanich ◽

Meena Gorowara ◽

Anchalee Avihingsanon ◽

Stephen J. Kerr ◽

Nadine van Heesch ◽

...

Keyword(s):

Maintenance Therapy ◽

Viral Suppression ◽

Low Dose ◽

Virologic Response ◽

Pharmacokinetic Data ◽

Time Curve ◽

Once Daily ◽

Hiv Rna ◽

The Mean ◽

To Receive

ABSTRACTBecause studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC0-12) was 15.6 mg/liter-h and the minimum plasma drug concentration (Ctrough) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC0-24was 33.6 mg/liter-h and theCtroughwas 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC0-24was 18.6 mg/liter-h and theCtroughwas 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC0-24for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC0-24and those on raltegravir at 400 mg QD had a similar AUC0-24. More patients had aCtroughof <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had lowCtroughvalues. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a lowCtroughand with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.

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Drug Interactions Between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine

10.1101/351684 ◽

2018 ◽

Author(s):

Stephen I Walimbwa ◽

Mohammed Lamorde ◽

Catriona Waitt ◽

Julian Kaboggoza ◽

Laura Else ◽

...

Keyword(s):

Maximum Concentration ◽

Geometric Mean ◽

Compartmental Analysis ◽

Sub Saharan Africa ◽

Pharmacokinetic Studies ◽

Serious Adverse Events ◽

Time Curve ◽

Once Daily ◽

Trough Concentrations ◽

Sub Saharan

ABSTRACTAcross sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for ARM, DHA, LF and DBL nor significantly alter AUC for ARS, DHA, AQ and DEAQ. Co-administration of dolutegravir with AL resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with AS-AQ resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. Study drugs were well-tolerated with no serious adverse events. Standard doses of artmether-lumefantrine and artesunate-amodiaquine should be used in patients receiving DTG. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and DTG exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above DTG target concentrations of 64ng/mL.

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Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01014-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 19

Author(s):

S. Dian ◽

V. Yunivita ◽

A. R. Ganiem ◽

T. Pramaesya ◽

L. Chaidir ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Tuberculous Meningitis ◽

Standard Dose ◽

Geometric Mean ◽

Phase Iii ◽

High Dose ◽

Treatment Area ◽

Double Blind ◽

Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

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Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial

Journal of Clinical Oncology ◽

10.1200/jco.2015.64.8899 ◽

2016 ◽

Vol 34 (20) ◽

pp. 2333-2340 ◽

Cited By ~ 339

Author(s):

Jorge E. Cortes ◽

Giuseppe Saglio ◽

Hagop M. Kantarjian ◽

Michele Baccarani ◽

Jiří Mayer ◽

...

Keyword(s):

Overall Survival ◽

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase Iii ◽

Blast Phase ◽

Once Daily ◽

Study Results ◽

Treatment Naïve

Purpose We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. Patients and Methods Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Results At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. Conclusion These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.

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Effect of Tipranavir-Ritonavir on Pharmacokinetics of Raltegravir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01486-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2752-2755 ◽

Cited By ~ 29

Author(s):

William D. Hanley ◽

Larissa A. Wenning ◽

Allison Moreau ◽

James T. Kost ◽

Eric Mangin ◽

...

Keyword(s):

Geometric Mean ◽

Study Drug ◽

Integrase Inhibitor ◽

Phase Iii ◽

Open Label ◽

Time Curve ◽

Period 2 ◽

Adverse Experiences ◽

Immunodeficiency Virus

ABSTRACT Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C 12) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C 12 was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.

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Improved Myocardial T2* in Transfusion Dependent Anemias Receiving ICL670 (Deferasirox).

Blood ◽

10.1182/blood.v106.11.3600.3600 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3600-3600 ◽

Cited By ~ 16

Author(s):

John B. Porter ◽

Mark A. Tanner ◽

Dudley J. Pennell ◽

Perla Eleftheriou

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Geometric Mean ◽

Randomized Study ◽

Iron Concentration ◽

T Test ◽

Phase Iii ◽

Once Daily ◽

Paired Student ◽

Wide Range

Abstract ICL670 (deferasirox) is an orally active iron chelator, intended as once daily mono-therapy for the treatment of transfusional iron overload, which has undergone extensive multi-centre Phase II and Phase III trials. Data from such studies suggest that 20mg/kg as a single daily dose will achieve iron balance in the majority of transfusionally dependent patients, whereas 30mg/kg/day typically achieves negative iron balance (Cappellini, Abstract 3619, ASH 2004) (Porter, Abstract 3193, ASH 2004). Patients with transfusion dependent anaemia and iron overload who were entered into these multi-centre studies at UCL Hospitals had myocardial T2* CMR performed at the Royal Brompton Hospital, as part of their routine monitoring, in line with previous clinical management at our centre. Study 108, a non-randomized study, included poorly chelated patients with -thalassemia and other iron overload conditions receiving regular blood transfusion: all patients received 10-30mg/kg/day of ICL670. Study 107 consisted exclusively of transfusion dependent -thalassemia patients, randomized to receive either 8–10h sc DFO (30–50mg/kg/day) or ICL670 (10–30mg/kg/day) with doses stratified for baseline liver iron concentration (LIC). We report here changes in cardiac T2*, LIC and serum ferritin, as well as LVEF in all patients on these two studies treated at UCLH for a mean of 13.1± 0.78 months, in whom CMR was obtained. In a total of 23 patients treated with ICL670, mean age 24.6y (range 9–50y), 18 with transfusion dependent -thalassaemia and 6 other iron overload conditions (2 Pyruvate kinase deficiency, 2 sideroblastic anemia, 2 Diamond Blackfan Anemia), myocardial T2* improved significantly from a pre-treatment geometric mean of 18.0ms to 23.1ms (p = 0.013, paired student t test). In the same patients, serum ferritin fell significantly from 3173 ±410 μg/L to 2451 ±242μg/L (p= 0.023, paired student t test) and LIC fell significantly from 18.3 ±2.2 mg/g dry wt to 10.0 ±1.49 (p= 0.0002, paired student t test). There was no significant change in LVEF before or after treatment over the same period. Patients treated in the DFO arm of study 107 (n=8) also showed a small non-significant increase in myocardial T2* from 18.1 ms to 21.1 ms (p= 0.11), These studies suggest that once daily mono-therapy with ICL670 will be effective at improving myocardial T2* and by inference myocardial iron loading in a wide range of patients with transfusional iron overload. Prospective randomised controlled studies in larger patient numbers are now indicated.

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Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01136-06 ◽

2007 ◽

Vol 51 (6) ◽

pp. 2035-2042 ◽

Cited By ~ 7

Author(s):

Ana Marin-Niebla ◽

Luis Fernando Lopez-Cortes ◽

Rosa Ruiz-Valderas ◽

Pompeyo Viciana ◽

Rosario Mata ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitor ◽

Virological Failure ◽

Low Dose ◽

Pharmacokinetic Data ◽

Time Curve ◽

Once Daily ◽

Intention To Treat ◽

Immunodeficiency Virus ◽

Treatment Naïve

ABSTRACT We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10 copies/ml. Median C max, area under the concentration-time curve from 0 to 24 h, and C min plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate C min levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.

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Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01310-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01310-18 ◽

Cited By ~ 4

Author(s):

Stephen I. Walimbwa ◽

Mohammed Lamorde ◽

Catriona Waitt ◽

Julian Kaboggoza ◽

Laura Else ◽

...

Keyword(s):

Maximum Concentration ◽

Geometric Mean ◽

Sub Saharan Africa ◽

Pharmacokinetic Studies ◽

Noncompartmental Analysis ◽

Serious Adverse Events ◽

Time Curve ◽

Once Daily ◽

Trough Concentrations ◽

Sub Saharan

ABSTRACT Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.)

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