The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society–USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

Abstract Background Cardiometabolic outcomes were investigated 3 years after switching to the 2-drug regimen dolutegravir/lamivudine (DTG/3TC) vs continuing 3-/4-drug tenofovir alafenamide (TAF)–based regimens in a multicenter phase 3 noninferiority study based on an open-label randomized design. Method Adults with virologically suppressed HIV-1 switched to once-daily DTG/3TC (n = 369) or continued TAF-based regimens (n = 372). Cardiometabolic health parameters were assessed through week 144 via mixed-model repeated measures or logistic regression analyses, adjusting for baseline variables. Results At week 144, 13% (42/316) of the DTG/3TC group and 12% (37/303) of the TAF-based regimen group had ≥10% weight gain from baseline (adjusted odds ratio, 1.11; 95% CI, .68–1.80). Adjusted change from baseline in serum leptin, a surrogate marker of adiposity, was similar between groups (treatment ratio, 1.00; 95% CI, .89–1.13). The lipid profile generally favored DTG/3TC in the baseline boosted subgroup. Adjusted odds revealed no clinically meaningful differences between groups: homeostatic model assessment of insulin resistance ≥2 (adjusted odds ratio, 0.79; 95% CI, .50–1.26), metabolic syndrome (International Diabetes Federation criteria, 0.99; .59–1.68), hepatic fibrosis (fibrosis-4 index score ≥1.45, 1.39; .63–3.06), and coronary artery disease risk (Framingham risk score ≥10%, 0.92; .56–1.49). Baseline variables and characteristics associated with odds of each cardiometabolic parameter outcome were consistent with known risk factors, including age, sex, race, and some disease characteristics. Conclusions Cardiometabolic health 3 years after switching to DTG/3TC was comparable to that for individuals continuing TAF-based regimens, further supporting DTG/3TC as a robust switch option with a stable metabolic profile. Trial registration ClinicalTrials.gov NCT03446573

Switching to dolutegravir/lamivudine (DTG/3TC), versus continuing tenofovir alafenamide-based regimens, showed durable efficacy and safety through 144 weeks, with no virologic failure or resistance detected, supporting the use of DTG/3TC in virologically suppressed individuals with human immunodeficiency virus type 1. Background Switching to dolutegravir/lamivudine (DTG/3TC) was noninferior to continuing tenofovir alafenamide (TAF)-based regimens for maintaining virologic suppression at week 48 of the TANGO study. Here we present week 144 outcomes (efficacy, safety, weight, and biomarkers). Methods TANGO is a randomized (1:1, stratified by baseline third agent class), open-label, noninferiority phase 3 study. Virologically suppressed (>6 months) adults with human immunodeficiency virus type 1 (HIV-1) switched to once-daily DTG/3TC or continued TAF-based regimens. Results A total of 741 participants received study treatment (DTG/3TC, n = 369; TAF-based regimen, n = 372). At week 144, the proportion of participants with an HIV-1 RNA level >= 50 copies/mL (primary end point, Snapshot; intention-to-treat-exposed population) after switching to DTG/3TC was 0.3% (1 of 369) versus 1.3% (5 of 372) for those continuing TAF-based regimens, demonstrating noninferiority (adjusted treatment difference, -1.1 [95% confidence interval, -2.4 to .2), with DTG/3TC favored in the per-protocol analysis (adjusted treatment difference, -1.1 [-2.3 to -.0]; P = .04). Few participants met confirmed virologic withdrawal criteria (none in the DTG/3TC and 3 in the TAF-based regimen group), with no resistance observed. Drug-related adverse events were more frequent with DTG/3TC (15%; leading to discontinuation in 4%) than TAF-based regimens (5%; leading to discontinuation in 1%) through week 144, but rates were comparable after week 48 (4%; leading to discontinuation in 1% in both groups). Changes from baseline in lipid values generally favored DTG/3TC; no clinical impact on renal function and comparable changes in inflammatory and bone biomarkers across groups were observed. Conclusions Switching to DTG/3TC demonstrated noninferior and durable efficacy compared with continuing TAF-based regimens in treatment-experienced adults with HIV-1, with good safety and tolerability, and no resistance through 144 weeks.

Dolutegravir/Lamivudina (DTG / 3TC) é um regime completo de 2 medicamentos (2DR) para o tratamento do HIV-1. A eficácia virológica não inferior foi comprovada ao longo de 3 anos em pessoas virgens de tratamento PARA HIV e 2 anos em um ambiente de troca estável. TANGO, um estudo randomizado, aberto e de não inferioridade, avalia a eficácia e a segurança da mudança para DTG/3TC em adultos virologicamente suprimidos (> 6 meses, sem falha virológica anterior, sem resistência maior a INI ou ITRN) vs permanecer em um regime baseado em tenofovir alafenamida (TBR) de 3 ou 4 medicamentos, estratificado pela 3ª classe de agente basal. As análises da semana 144 avaliaram a não inferioridade (margem de 4% para falha virológica e 8% para sucesso virológico; análise de snapshot, intenção de tratar na população exposta [ITT-E]). De 741 participantes randomizados/expostos (DTG/3TC, 369; TBR, 372), a maioria entrou no estudo com elvitegravir/cobicistate (66%). Na semana 144, a mudança para DTG/3TC foi não inferior à continuação da TBR (falha virológica snapshot, ITT-E): 0,3% vs 1,3%; diferença ajustada (IC 95%): -1,1% (-2,4%, 0,2%) e superior à TBR na análise por protocolo: 0% vs 1,1%; diferença ajustada: -1,1% (-2,3%, -0,0%); p = 0,044 (bilateral). O sucesso virológico por snapshot foi alto em ambos os braços, demonstrando não inferioridade (DTG/3TC, 85,9% vs TBR, 81,7%; diferença ajustada [IC de 95%]: 4,2% [-1,1%, 9,5%]). Nenhum participante no DTG/3TC e 3 (0,8%) no TBR preencheram os critérios de retirada por falha virológica confirmada sem resistência observada. Nenhum participante em DTG/3TC e 6 (1,6%) em TBR descontinuaram por falta de eficácia. As taxas gerais de eventos adversos foram semelhantes entre os braços (DTG/3TC, 91%; TBR, 90%). Colesterol total (CT), colesterol LDL e triglicerídeos melhoraram com DTG/3TC, colesterol HDL melhorou com TBR, sem diferença na razão TC/HDL entre os braços. As alterações nos biomarcadores renais foram semelhantes entre os braços. A alteração média ajustada da linha de base no peso foi de 2,2 kg com DTG/3TC e 1,7 kg com TBR, e a proporção de participantes com aumento de peso ≥10% foi semelhante (DTG / 3TC, 13%; TBR, 12%). Mudar para DTG/3TC de um TBR de 3 ou 4 medicamentos resultou em eficácia elevada e não inferior, sem falhas virológicas confirmadas e boa tolerabilidade ao longo de 3 anos de tratamento. DTG/3TC é uma opção robusta com eficácia durável, boa segurança e tolerabilidade e uma alta barreira à resistência.

Abstract Background DTG/3TC is a complete 2-drug regimen (2DR) for the treatment of HIV-1 infection. Non-inferior virologic efficacy has been proven over 3 years in treatment-naive people living with HIV (PLWH) and 2 years in a stable switch setting. Methods TANGO, a randomized, open-label, non-inferiority study, evaluates efficacy and safety of switching to DTG/3TC in PLWH who are virologically suppressed ( > 6 months, no prior virologic failure [VF], no major NRTI/INSTI resistance) vs remaining on a 3- or 4-drug TAF-based regimen (TBR), stratified by baseline 3rd agent class. Week 144 analyses assessed non-inferiority (NI) with a 4% NI margin for Snapshot virologic failure (VF) and 8% for virologic success (VS; FDA Snapshot algorithm, intention-to-treat–exposed [ITT-E] population). Results Of 741 randomized/exposed pts (DTG/3TC: 369; TBR: 372), most pts entered the study on EVG/c (66%). For Week 144 Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR in the ITT-E analysis: 0.3% vs 1.3%; adjusted difference (95% CI): −1.1% (−2.4%, 0.2%) and superior to TBR in the per-protocol analysis: 0% vs 1.1%; adjusted difference: −1.1% (−2.3, −0.0); P=0.044 (2-sided). Snapshot VS was high in both arms and demonstrated non-inferiority (Table). Zero pts on DTG/3TC and 3 (0.8%) on TBR met confirmed virologic withdrawal criteria with no resistance observed. Zero pts on DTG/3TC and 6 (1.6%) on TBR discontinued for lack of efficacy. Overall AE rates were similar between arms (Table). TC, LDL-C, and triglycerides improved with DTG/3TC, HDL-C improved with TBR, with no difference in TC/HDL-C ratio between arms. Changes in eGFR (cystatin C) and proximal tubular function marker were similar across arms. Adjusted mean change from BL in weight was 2.2 and 1.7 kg in the DTG/3TC and TBR arms, respectively, and proportion of pts with > 10% weight increase was similar across arms (13% and 12%, respectively). Table. Efficacy and Key Safety Results for the ITT-E and Safety Population Conclusion Switching to the 2-drug regimen of DTG/3TC from a TAF-based 3- or 4-drug regimen resulted in high, non-inferior efficacy with zero confirmed virologic withdrawals and good tolerability over 3 years of treatment. DTG/3TC 2DR is a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance. Disclosures Olayemi Osiyemi, M.D, Gilead (Advisor or Review Panel member, Speaker’s Bureau)Merck (Advisor or Review Panel member)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Fiona Bisshop, MBBBS, Gilead (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Stéphane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Joaquín Portilla, MD, AbbVie (Other Financial or Material Support)Gilead (Grant/Research Support, Other Financial or Material Support)Janssen (Grant/Research Support, Other Financial or Material Support)Merck Sharpe & Dohme (Other Financial or Material Support)ViiV Healthcare (Grant/Research Support, Other Financial or Material Support) Jean-Pierre Routy, MD, FRCPC, ViiV Healthcare (Grant/Research Support) Mounir Ait-Khaled, PhD, ViiV Healthcare (Employee) Keith Pappa, PharmD, Glaxo Smith Kline (Shareholder)ViiV Healthcare (Employee) Ruolan Wang, Master of Science, ViiV Healthcare (Employee) Peter Leone, MD, viiv healthcare (Employee) Jonathan Wright, MSc, GlaxoSmithKline (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kimberly Smith, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Background: There is an overlap between problematic drug use, homelessness, and sex work. During the COVID crisis, an increasing number of women have fallen into homelessness and street-based sex work due to financial instability. There is an ongoing need for sexual health, drug treatment, and housing interventions to support these vulnerable women. Find and Treat, mobile homeless health service, UCLH initiated pilot work in collaboration with the sexual health sex work outreach team, CLASH, from Mortimer Market Centre. Method: Outreach testing sessions took place in North London at a location where clients were engaging in street-based sex work. All clients were offered pregnancy testing, point of care testing for HIV, hepatitis C and syphilis All were offered STI screening for Neisseria gonorrhoea and Chlamydia trachomatis, using NAAT triple site testing. Emergency contraception and referral for HIV PrEP was offered to all who needed it. Patients were recalled for STI treatment. Results: So far, 23 clients have been screened, two male, one trans-female, and 20 females. 17/23(74%) reported homelessness (insecure housing or rough sleeping),8/23(34%) born in the UK.13/23(58%) reported current drug use, 10/23(43%) reported current injecting. All reported engagement in transactional sex. One client reported inter-menstrual bleeding, 22/23 clients reported no symptoms at the time of screening. 45 infections were identified in 21/23(91%) clients screened;6 syphilis antibody positive (confirmed on serology),4 HCV RNA+,19 CT infections (7 vaginal CT,8 rectal CT,4 pharyngeal CT),16 NG infections (7 vaginal NG,5 rectal NG,4 pharyngeal NG) 21/23(91%) clients had infection at more than one anatomical site. Conclusion: These pilot sessions have demonstrated a clear unmet need and overlap of homelessness, drug use and sex work. This client group is high risk for STIs and bloodborne viruses (BBVs), with 91% of people tested having infection. This high burden of infection will increase risk of complications for the individuals, transmission within the community, and risk of HIV acquisition. There is low rate of follow-up attendance in clinic, due to working hours of the clients, difficulty travelling to clinic and difficulty contacting the clients over the phone. Urgent intervention is needed to increase access to point of care testing, treatment and HIV PrEP in the outreach setting, to ensure equity of access to healthcare and to improve the health and wellbeing of vulnerable individuals.

Background: Dolutegravir/Lamivudine (DTG/3TC) 2-drug regimen (2DR) was non-inferior to a tenofovir alafenamide (TAF)-based 3-/ 4-drug regimen (3/4DR) (TBR) through the Week 48 primary endpoint in TANGO. Here we present prespecified Week 96 secondary analyses from TANGO. Method: TANGO, a randomized, open-label, non-inferiority phase III study, evaluates efficacy and safety of switching to once-daily DTG/3TC in HIV-1- infected, virologically suppressed adults vs remaining on a TBR over 148 weeks. Week 96 analysis assessed non-inferiority with a 4% non-inferiority margin for Snapshot virologic failure (VF) and 8% for virologic success (VS;US Food and Drug Administration Snapshot algorithm, intention-to- treat- exposed [ITT-E] population). Results: 741 participants were randomized/exposed (DTG/3TC: 369;TBR: 372). For Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR at Week 96 in the ITT-E analysis: 0.3% vs 1.1%;adjusted difference: -0.8% (95% CI: -2.0, 0.4) and superior to TBR in the per-protocol analysis: 0% vs 1.1%;adjusted difference: -1.1% (95% CI: -2.3, -0.0);P = 0.044 (2-sided). Snapshot VS was high in both arms (DTG/3TC: 85.9%;TBR: 79.0%;adjusted difference: 6.8% [95% CI: 1.4-12.3]). Forty-four participants (5.9%) had missing data in the Week 96 window due to COVID-19. No participants on DTG/3TC and 3 (<1%) on TBR met confirmed virologic withdrawal (CVW) criteria, with no resistance observed at failure. Overall adverse event (AE) rates were similar between arms, with more drug-related AEs in the DTG/3TC arm. Total cholesterol (TC), low-density lipoprotein cholesterol, and triglycerides improved significantly with DTG/3TC, whereas high-density lipoprotein (HDL) cholesterol changes significantly favored TBR, with no difference in TC/HDL-cholesterol ratio between arms. Decreases in glomerular filtration rate by cystatin C were observed with significantly lower decreases in the DTG/3TC arm;proximal tubular function marker changes were small and similar across arms. Conclusion: At Week 96, switching to DTG/3TC FDC was non-inferior to continuing a TAF-based 3/4DR in maintaining virologic suppression in HIV-1- infected antiretroviral therapy-experienced adults. The safety profile of DTG/3TC FDC was consistent with the DTG and 3TC respective labels. DTG/3TC 2DR offers a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance with zero CVWs through 96 weeks.

Background: In TANGO, switching to dolutegravir/lamivudine was noninferior at 48 weeks to continuing 3-/4-drug tenofovir alafenamide–based regimens in virologically suppressed individuals with HIV-1. Antiretroviral agents have been associated with weight gain and metabolic complications. Setting: One hundred thirty-four centers; 10 countries. Methods: We assessed weight; fasting lipids, glucose, and insulin; and prevalence of insulin resistance and metabolic syndrome at baseline and week 48 in TANGO participant subgroups by boosting agent use in baseline regimens (boosted and unboosted). Results: In each treatment group, 74% of participants used boosted regimens at baseline. In boosted and unboosted subgroups, weight and fasting glucose changes at week 48 were small and similar between treatment groups. Overall and in the boosted subgroup, greater decreases from baseline were observed with dolutegravir/lamivudine in fasting total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), total cholesterol/high-density lipoprotein cholesterol ratio (overall, P = 0.017; boosted, P = 0.007), and insulin (boosted, P = 0.005). Prevalence of HOMA-IR ≥2 was significantly lower at week 48 with dolutegravir/lamivudine overall [adjusted odds ratio (aOR), 0.59; 95% confidence interval (CI), 0.40 to 0.87; P = 0.008] and in the boosted subgroup [aOR, 0.56; 95% CI, 0.36 to 0.88; P = 0.012] but not in the unboosted subgroup [aOR, 0.70; 95% CI, 0.31 to 1.58; P = 0.396]. Prevalence of metabolic syndrome at week 48 was low and consistent between treatment groups overall, with differences trending to favor dolutegravir/lamivudine in the unboosted subgroup [aOR, 0.41; 95% CI, 0.15 to 1.09; P = 0.075]. Conclusion: Generally, switching from 3-/4-drug tenofovir alafenamide–based regimens to dolutegravir/lamivudine improved metabolic parameters, particularly when switching from boosted regimens. Because of smaller sample size in the unboosted subgroup, results warrant further investigation.

Abstract Background The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals. Methods TANGO is an open-label, multicenter, phase 3 study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or remain on a tenofovir alafenamide (TAF)–based regimen. The primary end point was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48 (US Food and Drug Administration Snapshot algorithm) in the intention-to-treat–exposed population (4% noninferiority margin). Results 743 adults were enrolled; 741 received ≥1 dose of study drug (DTG/3TC, N = 369; TAF-based regimen, N = 372). At week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL receiving DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% confidence interval], −0.3 [−1.2 to .7]), meeting noninferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at failure. Drug-related grade ≥2 adverse events and withdrawals due to adverse events occurred in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively. Conclusions DTG/3TC was noninferior in maintaining virologic suppression vs a TAF-based regimen at week 48, with no virologic failure or emergent resistance reported with DTG/3TC, supporting it as a simplification strategy for virologically suppressed people with HIV-1. Clinical Trials Registration NCT03446573.

Background: DTG/3TC two-drug regimen (2DR) was non-inferior to a TAF-based 3/4DR through the Week 48 primary endpoint in TANGO Here we present Week 96 secondary endpoint analyses Materials and methods: TANGO, a randomized, open-label, non-inferiority phase III study evaluates the efficacy and safety of switching to once-daily DTG/3TC in HIV-1-infected, virologically suppressed (\u003e6 months, no prior virologic failure, no major NRTI or INSTI resistance) adults versus remaining on a TBR, over 148 weeks Participants were randomized 1:1, stratified by baseline third agent class: PI, NNRTI, INSTI Week 96 analysis assessed non-inferiority with a 4% non-inferiority margin for Snapshot virologic failure (VF) and 8% for virologic success (VS;FDA Snapshot algorithm, intention-to-treat-exposed [ITT-E] population) Results: Seven hundred and forty-one randomized/exposed participants (DTG/3TC: 369;TBR: 372) For Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR at Week 96 in the ITT-E analysis: 0 3% versus 1 1%;adjusted difference:-0 8% (95% CI-2 0%, 0 4%) and superior to TBR in the per-protocol analysis: 0% versus 1 1%;adjusted difference:-1 1% (95% CI-2 3%,-0 0%);p = 0 044 (twosided) Snapshot VS was high in both arms and demonstrated non-inferiority (Table 1) Forty-four participants (5 9%) had missing data in the Week 96 window due to COVID-19 impact Zero participants on DTG/3TC and three (\u003c1%) on TBR met protocol-defined VF with no resistance observed at failure Overall adverse event (AE) rates were similar between arms, with more drug-related AEs in the DTG/3TC arm (Table 1) TC, LDL-cholesterol, and triglycerides improved significantly with DTG/3TC while HDL-cholesterol (HDL-C) changes significantly favored TBR, with no difference in TC/HDL-C ratio between arms Decreases in GFR by cystatin C were observed with a significantly lower decrease in the DTG/3TC arm;proximal tubular function marker changes were small and similar across arms aSnapshot virologic success adjusted difference in (DTG/3TC)-TBR: 6 8% (95% CI 1 4%, 12 3%) Estimates and confidence intervals were based on a stratified analysis using Cochran-Mantel-Haenszel weights adjusting for baseline third agent class;bsensitivity analysis excluding 16 and 28 participants in the DTG/3TC and TBR arms, respectively, because of no Week 96 HIV-1 RNA data due to COVID-19 pandemic impact Snapshot virologic success adjusted difference in (DTG/3TC)-TBR: 4 3% (95% CI-0 6%, 9 2%);cone participant was excluded due to receiving a TDF-based regimen instead of a TAF-based regimen;dtwo deaths (one homicide and one unknown reason) both unrelated to treatment occurred in the DTG/3TC arm Conclusions: At Week 96, switching to DTG/3TC FDC was non-inferior to continuing a TAF-based 3/4DR in maintaining virologic suppression in HIV-1-infected ART-experienced adults The safety profile of DTG/3TC FDC was consistent with the DTG and 3TC respective labels DTG/3TC 2DR offers a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance with zero protocol-defined VF through 96 weeks

Purpose: The purpose of this randomized, two-period crossover study was to determine the pharmacokinetics of orally administered topotecan in the presence and absence of oral ranitidine. Methods: Patients with solid malignant tumors refractory to standard treatment were given topotecan orally on a daily times five schedule repeated every 21 days. Topotecan was given initially at 2.3 mg/m2 per day; dose adjustments were permitted after the first dose of course 2 if necessary. Blood samples for pharmacokinetic assessments were drawn at protocol-specified times for up to 10 h following oral administration of topotecan on day 1 of courses 1 and 2. Patients were randomly assigned to receive a total of nine doses of ranitidine: 150 mg twice daily for 4 days before day 1 of one of the first two courses and 150 mg given 2 h before the first topotecan dose. Plasma samples were assayed for concentrations of active topotecan lactone (TPT-L) and total topotecan (TPT-T, lactone plus open-ring carboxylate form) using high-performance liquid chromatography with fluorescence detection. After completion of courses 1 and 2, patients could continue on therapy for days 1–5 of every 21 days if not withdrawn due to unacceptable toxicity, disease progression, protocol violation, or by request. Patients continued on treatment for a maximum of six courses. Results: No pharmacokinetic parameter for either TPT-L or TPT-T differed significantly during administration of topotecan with ranitidine compared with topotecan alone (n=13). Geometric mean ratios (95% confidence intervals, CIs) of areas under the curve in the presence and absence of ranitidine were 0.94 (0.80, 1.10) for TPT-L and 0.97 (0.80, 1.16) for TPT-T. Corresponding ratios (CIs) of peak plasma concentrations in the presence and absence of ranitidine were 1.06 (0.78, 1.44) for TPT-L and 1.07 (0.84, 1.38) for TPT-T. The median difference in time to peak plasma concentration was 0.0 h for TPT-L and −0.5 h for TPT-T (i.e. slightly faster in the presence of ranitidine). Conclusions: Administration of ranitidine prior to oral topotecan resulted in a similar extent of absorption. A slightly faster rate of absorption of topotecan was also observed, which is unlikely to be of clinical significance. Dosage adjustments of orally administered topotecan should not be necessary in patients who are pretreated with ranitidine, an H2 antagonist, or another agent that comparably raises gastric pH.