Reduced Drug Exposure Research Articles

Taste of a Pill

Drug-induced taste disturbance is a common adverse drug reaction often triggered by drug secretion into saliva. Very little is known regarding the molecular mechanisms underlying salivary gland transport of xenobiotics, and most drugs are assumed to enter saliva by passive diffusion. In this study, we demonstrate that salivary glands selectively and highly express OCT3 (organic cation transporter-3), a polyspecific drug transporter in the solute carrier 22 family. OCT3 protein is localized at both basolateral (blood-facing) and apical (saliva-facing) membranes of salivary gland acinar cells, suggesting a dual role of this transporter in mediating both epithelial uptake and efflux of organic cations in the secretory cells of salivary glands. Metformin, a widely used anti-diabetic drug known to induce taste disturbance, is transported by OCT3/Oct3 in vitro. In vivo, metformin was actively transported with a high level of accumulation in the salivary glands of wild-type mice. In contrast, active uptake and accumulation of metformin in salivary glands were abolished in Oct3(-/-) mice. Oct3(-/-) mice also showed altered metformin pharmacokinetics and reduced drug exposure in the heart. These results demonstrate that OCT3 is responsible for metformin accumulation and secretion in salivary glands. Our study uncovered a novel carrier-mediated pathway for drug entry into saliva and sheds new light on the molecular mechanisms underlying drug-induced taste disorders.

Limustin®, a non-innovator tacrolimus formulation, yields reduced drug exposure in pediatric renal transplant recipients.

The aim of this study was to evaluate the bioavailability of two oral tacrolimus formulations, the innovator Prograf(®) and a formulation commercialized in Mexico with the brand name Limustin(®), in children. Stable Mexican pediatric renal transplant recipients received the product authorized by their social security provider, being either Prograf(®) or Limustin(®). At steady state, blood samples were drawn and tacrolimus blood concentration against time curves was constructed. CYP3A5 genotype was also determined. There was no significant difference in dose or in trough concentrations between formulations. However, AUC and Cmax were significantly higher with Prograf(®). The lower tacrolimus bioavailability with Limustin(®) was observed in both expressers and non-expressers of the functional CYP3A5 protein. Dose-normalized AUC values in expressers were 12.7 ± 11.9 and 48.7 ± 20.4 ng·h/mL/mg for Limustin(®) and Prograf(®), whereas in non-expressers, dose-normalized AUC was 54.4 ± 49.1 and 110.4 ± 42.9 ng·h/mL/mg for Limustin(®) and Prograf(®), respectively (p < 0.05). Pharmaceutical quality analysis showed that Limustin(®) dissolution at 120 min was 31.1 ± 6.2% while Prograf(®) dissolution was 100 ± 4.8%. Furthermore, the mean percentage of labeled amount of Limustin(®) and Prograf(®) was 91.0 ± 3.1% and 100.0 ± 0.7%, respectively. Hence, Limustin(®) exhibits pharmaceutical characteristics dissimilar to the innovator that likely explain the reduced tacrolimus exposure in children. We consider Limustin(®) is not adequate for pediatric use.

A new concept for the treatment of atopic dermatitis: Silver–nanolipid complex (sNLC)

In the treatment of mild to medium severe atopic dermatitis a new formulation proved to be highly efficient. The formulation is based on a combination of microsilver and nanolipid carriers (NLC) incorporated into an o/w cream and a lotion. A theory of action was proposed, the formation of silver-NLC complex (sNLC). In this study this theory was proven, and based on this new mechanism two new approaches for dealing with AD are suggested to distinctly improve AD treatment, i.e. increasing efficiency, reducing drug exposure and reducing side effects. The antimicrobial silver ions adsorb onto the surface of the negatively charged NLC (=sNLC complex). The sNLC as nanoparticles are highly adhesive to skin and bacterial surfaces, leading to a locally high concentration of silver ions killing the bacteria, much more effective than silver alone. The NLC restore the distorted skin barrier. Based on this a new two-step approach is suggested: (1) "treatment-supportive consumer care" by restoring the normal skin condition (NLC for barrier restoration plus synergistic antibacterial silver-NLC complex) and (2) "drug-loaded consumer care AD formulations". i.e. incorporating drugs into the NLC of this consumer care formulation. NLC incorporation makes the drugs more effective (penetration enhancement) and simultaneously exploits the skin normalization ability of the skin care sNLC formulation, future drug candidates being prednicarbate and tacrolimus.

Predicting treatment response in psoriasis using serum levels of adalimumab and etanercept: a single-centre, cohort study

A substantial proportion of patients with psoriasis do not respond, or lose initial response to tumour necrosis factor-α antagonists. One possible mechanism relates to subtherapeutic drug levels due to an immunogenic antibody response. To investigate the association between serum adalimumab and etanercept levels, antidrug antibody levels and clinical response in a cohort of patients with psoriasis using a commercially available enzyme-linked immunoassay. In a single-centre cohort of 56 adults with chronic plaque psoriasis initiated on adalimumab or etanercept monotherapy between 2009 and 2011, drug and antidrug antibody levels were measured at the patients' routine clinic reviews (4, 12 and 24 weeks of treatment and the last available observation). Patients' responses at 6 months were stratified into responders [75% reduction in Psoriasis Area and Severity Index from baseline (PASI 75) or Physician's Global Assessment score of 'clear' or 'nearly clear'] and nonresponders (failure to achieve PASI 50). After 4 weeks, adalimumab levels were significantly higher in responders compared with nonresponders (P = 0·003) and these higher levels were sustained at 12 and 24 weeks. Anti adalimumab antibodies were detected in 25% of nonresponders (two of eight patients, average 22·5 weeks' follow-up) and none of the responders (n = 23, average 26·1 weeks' follow-up). There was no significant association between etanercept levels and clinical response at 4 weeks (P = 0·317) and no antietanercept antibodies were detected. Lack of serum trough levels may have resulted in underestimation of the prevalence of antidrug antibodies. Early adalimumab drug level monitoring at 4 weeks may be useful in predicting treatment response and potentially reduce drug exposure (and associated cost) with earlier review of treatment in those with low levels. No conclusions about the value of etanercept drug monitoring can be made due to the paucity of data. Larger studies are now required to assess the clinical utility and cost-effectiveness of these assays in personalizing therapy in psoriasis.

Effects of Obesity on Posaconazole Kinetics in a Patient with Graft versus Host Disease

Posaconazole, a triazole antifungal agent, displays a highly variable pharmacokinetic profile due in part to the oral solution, the only currently available dosage form. Posaconazole activity appears to be dose-dependent and clinical outcomes correlate with steady-state serum trough concentrations and area under the concentration curve (AUC) over minimum inhibitory concentration (MIC) ratios. Therapeutic drug monitoring (TDM) has been recommended to help overcome the unpredictable nature of the drug. The impact of obesity of posaconazole pharmacokinetics and the use of TDM in this population has not been well described; however, limited data demonstrate increased weight correlates with lower serum concentrations and reduced drug exposure. We describe the use of TDM in an obese man, 12 months status post hematopoietic stem-cell transplant (HSCT), receiving posaconazole therapy for a presumed invasive fungal infection (IFI).

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

BackgroundMalaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda.MethodsTwenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.ResultsThe treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches.ConclusionThe population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Human interferon (IFN) β has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN β-1a (PEG-IFN β-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN β-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN β-1a and PEG-IFN β-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN β-1a showed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN β-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN β-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN β-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 μg/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 μg/kg (11 MIU/kg), the highest dose tested.

A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems

The pharmacokinetics, biodistribution, and antitumor efficacy of three doxorubicin formulations (doxorubicin in saline, conjugated to a polylysine dendrimer, and encapsulated within a stealth liposome) were investigated in Walker 256 tumor-bearing rats. Liposomal and dendrimer-based delivery systems resulted in more prolonged plasma exposure of total doxorubicin when compared to administration of doxorubicin in saline, although concentrations of free doxorubicin remained low in both cases. Biodistribution profiles revealed enhanced accumulation of dendrimer- and liposome-associated doxorubicin in tumors when compared to doxorubicin alone, although all three doxorubicin formulations reduced tumor growth to a similar extent. Markers of systemic toxicity (spleen weight, white blood cell counts, body weight, and cardiotoxicity) were more pronounced in rats that received doxorubicin and liposomal doxorubicin when compared to dendrimer-doxorubicin. The data provide preliminary evidence that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity (resulting from reduced drug exposure to nontarget organs). From the Clinical Editor In this manuscript, three different doxorubicin preparations are compared and preliminary evidence suggests that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity.

The Influence of Electroporation on in Vitro Photodynamic Therapy of Human Breast Carcinoma Cells

Phototoxicity of drugs used in cancer photodynamic therapy could be augmented by increased accumulation of a photosensitizer in target cells. The intracellular delivery mode that enhances drug transportation could facilitate therapy by reducing the exposure time. Doses of the administered drug and related side effects could be lowered, whilst maintaining the same therapeutic efficiency. Electroporation supports transport of many drugs by creating electric field-induced transient nanopores in the plasma membrane. In this study, the electroporation-assisted transport of a photosensitizer was tested in vitro in human breast carcinoma cell lines: wild-type (MCF-7/WT) and doxorubicin-resistant (MCF-7/DOX). The efficacy of photodynamic therapy alone and in combination with electroporation was evaluated by cell viability with MTT test, using a haematoporphyrin derivative as a model. The data presented show up to 10-fold greater efficacy of the combined method, with very significantly reduced drug exposure times.

Cardioprotective effect of metoprolol and enalapril in doxorubicin‐treated lymphoma patients: A prospective, parallel‐group, randomized, controlled study with 36‐month follow‐up

Anthracyclines have contributed to a marked increase in survival in different types of cancer [1,2]. Unfortunately, they are associated with dose-dependent cardiotoxicity and heart failure (HF) [3–8]. Change to a weekly dosage schedule with slow infusions has been tested, a strategy that requires more frequent hospital visits and increased storage resources[7,9]. Liposomal anthracycline formulations with reduced drug exposure and lower plasma concentrations may still be cardiotoxic at higher cumulative doses [10]. Beta-blockers and angiotensin converting enzyme(ACE) inhibitors have been shown to reduce anthracycline-induced cardiotoxicity,but have not been tested in long-term prospective, randomized,controlled studies with well defined cardiotoxicity criteria and careful cardiac function monitoring [11–16]. We investigated doxorubicin-induced clinical or subclinical cardiotoxicity in lymphoma patients after concomitant prophylactic therapy with metoprolol or enalapril or no concomitant treatment. We examined whether cardiotoxicity was related to the treatment or any other variable. We found that HF was less frequent under concomitant treatment than no treatment, especially in the metoprolol group, but the differences were not significant. No association was found between the presence of cardiotoxicity and concomitant treatment or other variable apart of age that had a significant impact. The marginal benefit seen with metoprolol should be investigated further.

The Progression of a Novel Liposome-Based Delivery Vehicle Toward in vivo Drug Delivery

The primary aim of nanoscale drug delivery is to increase the efficacy of drug treatment by both lowering injected dose and reducing drug exposure to healthy tissue. Currently, liposomes are commonly used as carriers in industrial formulations for the treatment of cancer, but still suffer from drug retention and targeting issues. Previous work has established the vesosome, a large lipid bilayer enclosing multiple smaller liposomes, as an alternative to the liposome that offers improved retention and functionality.

Abbreviated, Dose Dense Fludarabine and Rituximab for Elderly Patients with Indolent B Cell Malignancies.

Abstract 4796 IntroductionTherapy for indolent B cell malignancies is primarily palliative. Therefore limiting toxicities by reducing drug exposure is desirable, particularly in elderly individuals. The combination of fludarabine and rituximab has been extensively used in patients with these disorders. We sought to decrease the number of fludarabine cycles, attempting to maintain the high response rates of this combination by increasing the doses of rituximab and the dose density. Patients and MethodsWe designed an abbreviated, but dose dense regimen (addFR) consisting of fludarabine 25 mg/m2/d for 5 days on weeks 1, 6 and 11 plus rituximab at 375mg/m2 on weeks 2-5 and 7-10. Maintenance was offered to responding patients with rituximab for 4 weekly doses every 6 months (for 2 years). This schema represents a 50% decrease in the dosage on fludarabine with a 33% increase in the dosage of rituximab compared to the standard regimen. Twelve patients with a median age of 70 years, (range 43 to 85, 9 of the 12 patient are older than 65 years of age) have been treated. Nine patients had chronic lymphocytic leukemia (CLL, n= 5) or small lymphocytic lymphoma (SLL, n= 4). Three patients had marginal zone lymphoma (MZL). Three patients had received prior therapy. Responses were assessed by standard criteria 4 weeks after completion of the planned 11 weeks of therapy. ResultsTwo patients are still completing their 11 weeks of therapy. Ten patients have completed the 11 weeks of addFR. They are evaluable for toxicity and responses. Hematological toxicities included neutropenia Grade >III in 2 patients with a single episode of neutropenic fevers requiring hospitalization. One patient with refractory disease was shown to have histological transformation from SLL to a diffuse large B cell lymphoma. All of the remaining 9 patients achieved a complete clinical remission, including 8 patients with CLL/SLL and 1 patient with MZL. With a median follow up of 13 months (range 10 to 23 months); these 9 patients have remained free of disease progression. ConclusionsaddFR seems to be well tolerated and effective even in patients older than 65 years of age. Experience with a larger number of patients and longer follow up is needed. Disclosures:No relevant conflicts of interest to declare.

A safety and feasibility study comparing an intermittent high dose with a daily standard dose of liposomal amphotericin B for persistent neutropenic fever

A high intermittent dose regimen (group A: 10 mg kg(-1) on day 1, 5 mg kg(-1) on days 3 and 6) was compared with standard dosing (group B: 3 mg kg(-1) per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (P=0.002), which extended the mean infusion time by 20 min (P=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUC(CREATININE)) for days 2-7 was 1.09 (P=0.27) and for days 2-14 was 1.05 (P=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), P=0.21], a higher AUC(POTASSIUM) (A : B ratio of 1.06, P=0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, P=0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), P<0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). Beta-D-Glucan levels were similar in both groups for patients without an IFI [AUC(GLUCAN) of 362 and 683 (P=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (P=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg(-1) on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg(-1) per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

Drug delivery trends in clinical trials and translational medicine: Updated analysis of ClinicalTrials.gov database

While the number of clinical trials has continued to grow by about 20% in the past six months, no corresponding growth in product approval by the food and drug administration is seen or anticipated in the near future. Late-stage clinical failures due to lack of efficacy or toxicity continues to be a challenge. The optimization of absorption, distribution, metabolism and elimination (ADME) has improved drug candidate selection and reduced early clinical failure. The current challenge is how to avoid late stage clinical failures. Expanded knowledge of drug target distribution, pharmacokinetics and validated biomarkers will allow implementation of appropriate drug delivery and clinical trial designs to reduce drug exposure to off-target organs such as the liver and kidney and could reduce potential untoward effects. In essence, integration of drug delivery and targeting to reduce exposure in off-target tissues in the preclinical and clinical program may hold the key to increasing the odds of success in drug development. In this update, we briefly review data on clinical trials pertinent to drug delivery in the current regulatory environment. It also provides our analysis on the emerging trends in second generation antibody therapeutics in drug delivery and targeting.

Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alfa‐2a plus ribavirin

The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice. To examine the impact of exposure to peginterferon alpha-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-naive patients with HCV genotype 1 infection enrolled in a large expanded access programme. Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (>or=75 kg) and peginterferon alpha-2a 180 microg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated. Mean ribavirin exposure in week 0-12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P < 0.001; SVR, 45% vs. 54%, respectively, P = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received (P < 0.001 for both). Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.

Managing Antiretroviral Therapy: Changing Regimens, Resistance Testing, and the Risks from Structured Treatment Interruptions

The management of patients receiving therapy for human immunodeficiency virus infection has improved in recent years owing to factors such as new classes of antiretroviral drugs, new agents in existing classes, and reduced resistance rates when chronically infected patients begin treatment with preferred regimens. Transmitted resistance variants in approximately 10% of treatment-naive patients underline the need for pretreatment resistance testing, to improve rates of virologic efficacy. Structured treatment interruptions to reduce drug exposure and toxicity should not be used outside well-controlled research studies, since this practice has been associated with increased rates of death and disease progression.

Trough plasma imatinib concentrations are associated with responses to standard-dose imatinib in chronic myeloid leukemia and could improve its clinical management

7027 Background: Variable responses to imatinib in the treatment of myelogenous leukemia (CML) are incompletely understood. Previous studies focused on cellular mechanisms of resistance to imatinib. Another hypothesis for variable response lies in pharmacokinetic variability that may reduce drug exposure in patients receiving imatinib. Methods: Using high- performance liquid chromatography-tandem mass spectrometry, we assessed trough plasma imatinib concentrations at steady state (Cmin) in more than 150 CML patients. Major molecular response (MMR) was defined as a 3 logarithm reduction of BCR-ABL transcripts, quantified from peripheral blood using Q-RTPCR. In addition, suboptimal response criteria defined by the European Leukemianet were used to increase doses of imatinib. Results: i) we assessed Cmin in 85 CML patients and demonstated a correlation with imatinib doses (median values 813, 1,135, 1,709 ng/ml for respectively 300,400, 600 mg/day). ii) for 68 patients after at least one year's treatment mean Cmin were significantly higher in the group with MMR (34 patients) than in the group without (1,452.1±649.1 ng per milliliter vs. 869.3±427.5 ng per milliliter, P&lt;0.001) whereas there was no difference in the imatinib daily dose. For Cmin and their discrimination potential for MMR, the area under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5 percent) and specificity (70.6 percent) at a plasma threshold of 1,002 ng per milliliter. iii) dose escalation of imatinid, 400mg up to 600mg was proposed in 8 patients in suboptimal response (3 according to cytogenetic criteria and 5 according to molecular criteria). The median Cmin increase from 573 ng/ml [181–1,376] to 1,139 ng/ml [733–2,262] and 5 patients had a cytogenetic (n=3) or a molecular (n=2) response. Conclusions: Monitoring of imatinib plasma levels could be very useful for the management of CML patients, or should at least be checked in the case of treatment failure or suboptimal response or in patients nonadherent with imatinib or with a drug-drug interaction suspicion. No significant financial relationships to disclose.

Limited Tissue Penetration of Taxanes: A Mechanism for Resistance in Solid Tumors

Limited drug penetration in solid tumors is a potential mechanism of resistance for many anticancer drugs. Taxanes represent a class of drugs that are currently undergoing a new round of development, but with little known of their ability to penetrate and distribute relative to blood vessels within solid tumors. We assessed the tissue penetration of paclitaxel and docetaxel in HCT-116 tumor xenografts and in multilayered cell culture (MCC), a three-dimensional cell culture model of the tumor extravascular compartment. In xenografts, taxanes were mapped relative to blood vessels to obtain drug profiles as a function of distance from vasculature. For MCC, cultures were exposed to stirred drug reservoirs and taxanes measured as a function of depth into tissue. Both taxanes exhibited limited penetration, with little drug reaching further than 100 microm into the tissue. Of the two, paclitaxel exhibited up to 2-fold greater penetration than docetaxel. Mapping tumor cell proliferation following treatment allowed the consequences of limited drug penetration to be assessed. In tumor xenografts where reduced drug exposure to cells far from vasculature is one of several factors influencing response to treatment, up to a 75% reduction in S-phase cells was achieved in cells nearest the vessels, but only 50% reduction was observed in the tissue 150 microm away. In MCC-based data, where the influence of reduced cell proliferation with depth into tissue was circumvented, a 5-fold (paclitaxel) and 10-fold (docetaxel) increase in reservoir drug concentration was required to produce a response in cells 150 microm into the tissue equivalent to that seen in cells directly exposed to the drug. These results indicate that limited distribution is an important mechanism of tumor resistance to taxanes.

Role of Structured Treatment Interruption in HIV Infection

Surprising results have been reported recently on the use of structured treatment interruptions (STIs) in two different situations in the management of HIV-1 infection. Interrupting therapy when the CD4+T-lymphocyte count is below 350 cells/mm3in order to reduce drug exposure was found to increase not only the risk of AIDS-related clinical events, but also the risk of cardiovascular and metabolic toxicities. This study called into question the use of the CD4+T-cell-guided treatment interruption approach in this patient population. On the other hand, evidence was presented of the ability of STIs to enhance anti-HIV-specific immunity in patients with chronic HIV-1 infection. This resulted in a small, but significant, fraction of patients gaining the ability to maintain low plasma levels of HIV-1 RNA without the need for antiretroviral chemotherapy.

Multiple-Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a Selective CXCR4 Receptor Inhibitor, in Human Subjects

AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.