Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Efficacy and safety of lanreotide autogel compared with lanreotide 40 mg prolonged release in Chinese patients with active acromegaly: results from a phase 3, prospective, randomized, and open-label study (LANTERN).

BACKGROUND: Lanreotide autogel is a somatostatin analog (SSA) approved for the treatment of acromegaly in 73 countries worldwide; however, it is not yet approved in China. The aim of this study was to evaluate the efficacy and safety of lanreotide autogel compared with lanreotide 40 mg prolonged release (PR) in Chinese patients with active acromegaly. METHODS: LANTERN was a phase 3, randomized, open-label, non-inferiority study. Patients with active acromegaly who had undergone surgery ≥3 months prior, or were unlikely or unable to undergo surgery, were treated with lanreotide autogel 60/90/120 mg (monthly deep subcutaneous injection) or lanreotide 40 mg PR (intramuscular injection every 7, 10, or 14 days) for 32 weeks. Primary endpoint was mean change-from-baseline in age-adjusted insulin-like growth factor-1 (IGF-1) standard deviation scores (SDS) at the end-of-study. Secondary endpoints included: growth hormone (GH) levels ≤2.5 µg/L or ≤ 1.0 µg/L, ≥20% reduction in tumor volume (TV) and safety. RESULTS: In total, 128 patients were randomized and received study treatment. Lanreotide autogel was non-inferior to lanreotide 40 mg PR: treatment difference (95% CI) for IGF-1 SDS between groups was - 0.32 (- 0.74, 0.11; per protocol population) and - 0.27 (- 0.63, 0.09; intention-to-treat [ITT] population), respectively. Reductions in IGF-1 (- 6.453 vs - 7.003) and GH levels (- 9.548 µg/L vs - 13.182 µg/L), and the proportion of patients with ≥1 acromegaly symptom (- 20.3% vs - 32.5%) were observed from baseline to end-of-study in lanreotide autogel and lanreotide 40 mg PR groups, respectively. In the lanreotide autogel group, 45.5% (25/55) patients achieved ≥20% reduction in TV compared with 50.9% (25/53) in lanreotide 40 mg PR group (ITT). Safety profiles were similar in both treatment groups. CONCLUSIONS: Lanreotide autogel was non-inferior to lanreotide 40 mg PR in Chinese patients with active acromegaly after 32 weeks of treatment. TRIAL REGISTRATION: Retrospectively registered on ClinicalTrials.gov: NCT02493517 (9 July 2015); prospectively registered on chinadrugtrials.org.cn: CTR20140698 (24 October 2014).

Intracellular nucleotide levels during coadministration of tenofovir disoproxil fumarate and didanosine in HIV-1-infected patients.

Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.

Pharmacological and safety profile of a prolonged-release lanreotide formulation in acromegaly.

BACKGROUND: Patients with acromegaly require lifelong medication; a longer dosing interval would reduce treatment burden. This study investigated the pharmacokinetics, pharmacodynamics and safety profile of a new prolonged-release formulation (PRF) of lanreotide every 12 weeks. RESEARCH DESIGN AND METHODS: In this multicenter, open-label, dose-ascending study, cohorts of nine patients with acromegaly received single doses of lanreotide PRF according to a 3 + 3 + 3 scheme in order to determine the maximum tolerated dose (MTD). Following a 12-week treatment period, patients were followed up for a further 12 weeks. Serum lanreotide, insulin-like growth factor-1 and growth hormone concentrations were analyzed. Adverse events were monitored throughout the study. RESULTS: The MTD was not reached. Peak lanreotide serum concentration values were similar in all cohorts, whereas area under the curve values from time zero to 85 days increased but were not dose-proportional. The apparent elimination half-life of lanreotide PRF was approximately 54-63 days, in line with the expected prolonged-release characteristics. Growth hormone and insulin-like growth factor-1 levels were generally stable. CONCLUSIONS: The safety and tolerability profile was in-line with the known safety profile of lanreotide autogel. Lanreotide PRF was well tolerated and the pharmacokinetic profile suggests that a dosing interval of 12 weeks could be achievable. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT02396953; EudraCT 2014-002389-62.

Effect of a short-term HAART on SIV load in macaque tissues is dependent on time of initiation and antiviral diffusion.

BACKGROUND: HIV reservoirs are rapidly established after infection, and the effect of HAART initiated very early during acute infection on HIV reservoirs remains poorly documented, particularly in tissue known to actively replicate the virus. In this context, we used the model of experimental infection of macaques with pathogenic SIV to assess in different tissues: (i) the effect of a short term HAART initiated at different stages during acute infection on viral dissemination and replication, and (ii) the local concentration of antiviral drugs. RESULTS: Here, we show that early treatment with AZT/3TC/IDV initiated either within 4 hours after intravenous infection of macaques with SIVmac251 (as a post exposure prophylaxis) or before viremia peak (7 days post-infection [pi]), had a strong impact on SIV production and dissemination in all tissues but did not prevent infection. When treatment was initiated after the viremia peak (14 days pi) or during early chronic infection (150 days pi), significant viral replication persists in the peripheral lymph nodes and the spleen of treated macaques despite a strong effect of treatment on viremia and gut associated lymphoid tissues. In these animals, the level of virus persistence in tissues was inversely correlated with local concentrations of 3TC: high concentrations of 3TC were measured in the gut whereas low concentrations were observed in the secondary lymphoid tissues. IDV, like 3TC, showed much higher concentration in the colon than in the spleen. AZT concentration was below the quantification threshold in all tissues studied. CONCLUSIONS: Our results suggest that limited antiviral drug diffusion in secondary lymphoid tissues may allow persistent viral replication in these tissues and could represent an obstacle to HIV prevention and eradication.

High levels of zidovudine (AZT) and its intracellular phosphate metabolites in AZT- and AZT-lamivudine-treated newborns of human immunodeficiency virus-infected mothers.

Newborns from human immunodeficiency virus-infected mothers are given antiretroviral prophylaxis against mother-to-child transmission, including predominantly nucleoside reverse transcriptase inhibitors. Pharmacological monitoring of these drugs in newborns has so far been limited to plasma and cord blood. In this study, samples from newborns (up to 45 days old) treated with zidovudine (AZT) alone (n = 29) or in combination with lamivudine (3TC) (n = 20) were analyzed for both intracellular concentrations of phosphate metabolites in peripheral blood mononuclear cells and levels of parent drugs in plasma. Plasma AZT and intracellular AZT-monophosphate and AZT-triphosphate (TP) concentrations were significantly higher during the first 15 days of life (199 versus 52.7 ng/ml [P < 0.0001], 732 versus 282 fmol/10(6) cells [P < 0.0001], and 170 versus 65.1 fmol/10(6) cells [P < 0.0001], respectively) and then became comparable to those of adults. No difference in intracellular AZT metabolite concentrations was found when AZT- and AZT-3TC-treated groups were compared. Plasma 3TC levels (lower limit of quantification [LLOQ], 1,157 ng/ml; median, 412.5 ng/ml) were not associated with the newborn's age, gender, or weight. Intracellular 3TC-TP concentrations (LLOQ, 40.4 pmol/10(6) cells; median, 18.9 pmol/10(6) cells) determined for newborns receiving the AZT-3TC combination were associated with neither the age nor weight of the newborns. Concentrations in females were significantly higher (1.8-fold [P = 0.0415]) than those in males. Unexpectedly, newborns on AZT monotherapy whose mothers' treatment included 3TC displayed residual plasma 3TC and intracellular 3TC-TP levels up to 1 week after birth.

Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects.

The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of human immunodeficiency virus infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged (>or=1- to 13-year) daily subcutaneous TFV regimens. The likelihood of renal toxicity (proximal renal tubular dysfunction [PRTD]) correlated with plasma drug concentrations, which depended on the dosage regimen and age-related changes in drug clearance. Below a threshold area under the concentration-time curve for TFV in plasma of approximately 10 microg x h/ml, an exposure severalfold higher than that observed in humans treated orally with 300 mg TFV disoproxil fumarate (TDF), prolonged TFV administration was not associated with PRTD based on urinalysis, serum chemistry analyses, bone mineral density, and clinical observations. At low-dose maintenance regimens, plasma TFV concentrations and intracellular TFV diphosphate concentrations were similar to or slightly higher than those observed in TDF-treated humans. No new toxicities were identified. The available evidence does not suggest teratogenic effects of prolonged low-dose TFV treatment; by the age of 10 years, one macaque, on TFV treatment since birth, had produced three offspring that were healthy by all criteria up to the age of 5 years. Despite the presence of viral variants with a lysine-to-arginine substitution at codon 65 (K65R) of RT in all 28 SIV-infected animals, 6 animals suppressed viremia to undetectable levels for as long as 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy.

Improved method to quantify intracellular zidovudine mono- and triphosphate in peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry.

The determination of intracellular triphosphate metabolites of nucleoside analogs used in anti-HIV therapy is very challenging. Despite the well-known sensitivity and selectivity of LC-MS/MS, the measurement of the triphosphate metabolite of zidovudine (AZT-TP) remains difficult because of the interferences induced by endogenous nucleotides triphosphates. We describe a new approach that allows improved determination of AZT-TP simultaneously with AZT-monophosphate (MP). This was obtained, first, by monitoring a transition from the molecular ion of AZT-TP to a minor but very specific product ion. Then, the spiking of samples with a constant amount of AZT-TP allowed the signal to emerge from background, leading to increased sensitivity. Finally, the analytical run time was reduced to less than 10 min. The low limits of quantification were at 150 and 300 fmol per sample for AZT-TP and AZT-MP, respectively. Recoveries were higher than 85%. Inaccuracy and precision were lower than 10% and 15% (17% at the limit of quantification), respectively. The new method offers the possibility of determining simultaneously other nucleotide phosphates, as shown here for d4T-TP (the triphosphate metabolite of another nucleoside analog, stavudine or d4T) and 2'-deoxythymidine-5'-triphosphate or dTTP (the corresponding natural nucleotide triphosphate).

Nucleotide analogue prodrug tenofovir disoproxil enhances lymphoid cell loading following oral administration in monkeys.

The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a dianion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell-permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine whether oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil's lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t(1/2)) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t(1/2) of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety enhances not only the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and give valuable insight for future prodrug development.

Evidence and possible consequences of the phosphorylation of nucleoside reverse transcriptase inhibitors in human red blood cells.

The intracellular metabolism of nucleoside reverse transcriptase inhibitors (NRTI) in mononuclear cells has been thoroughly studied, but that in red blood cells (RBC) has been disregarded. However, the phosphorylation of other analogous nucleosides (in particular, ribavirin) has been described previously. In this study, we investigated for the first time the phosphorylation of NRTI in human RBC. The presence of intracellular zidovudine (AZT) monophosphate, AZT triphosphate, lamivudine (3TC) triphosphate, and tenofovir (TFV) diphosphate, as well as endogenous dATP, dGTP, and dTTP, in RBC collected from human immunodeficiency virus-infected patients was examined. We observed evidence of a selective phosphorylation of 3TC, TFV, and endogenous purine deoxynucleosides to generate their triphosphate moieties. Conversely, no trace of AZT phosphate metabolites was found, and only faint dTTP signals were visible. A comparison of intracellular TFV diphosphate and 3TC triphosphate levels in RBC and peripheral blood mononuclear cells (PBMC) further highlighted the specificity of NRTI metabolism in each cell type. These findings raise the issue of RBC involvement in drug-drug interaction, drug pharmacokinetics, and drug-induced toxicity. Moreover, the typical preparation of PBMC samples by gradient density centrifugation does not prevent their contamination with RBC. We demonstrated that the presence of RBC within PBMC hampers an accurate determination of intracellular TFV diphosphate and dATP levels in clinical PBMC samples. Thus, we recommend removing RBC during PBMC preparation by using an ammonium chloride solution to enhance both the accuracy and the precision of intracellular drug monitoring.