A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin-integration of in vitro results, Phase I and Phase II data and model application for drug-drug interaction potential analysis.

PURPOSE: Zoptarelin doxorubicin is a fusion molecule of the chemotherapeutic doxorubicin and a luteinizing hormone-releasing hormone receptor (LHRHR) agonist, designed for drug targeting to LHRHR positive tumors. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) parent-metabolite model of zoptarelin doxorubicin and to apply it for drug-drug interaction (DDI) potential analysis. METHODS: The PBPK model was built in a two-step procedure. First, a model for doxorubicin was developed, using clinical data of a doxorubicin study arm. Second, a parent-metabolite model for zoptarelin doxorubicin was built, using clinical data of three different zoptarelin doxorubicin studies with a dosing range of 10-267 mg/m2, integrating the established doxorubicin model. DDI parameters determined in vitro were implemented to predict the impact of zoptarelin doxorubicin on possible victim drugs. RESULTS: In vitro, zoptarelin doxorubicin inhibits the drug transporters organic anion-transporting polypeptide 1B3 (OATP1B3) and organic cation transporter 2 (OCT2). The model was applied to evaluate the in vivo inhibition of these transporters in a generic manner, predicting worst-case scenario decreases of 0.5% for OATP1B3 and of 2.5% for OCT2 transport rates. Specific DDI simulations using PBPK models of simvastatin (OATP1B3 substrate) and metformin (OCT2 substrate) predict no significant changes of the plasma concentrations of these two victim drugs during co-administration. CONCLUSIONS: The first whole-body PBPK model of zoptarelin doxorubicin and its active metabolite doxorubicin has been successfully established. Zoptarelin doxorubicin shows no potential for DDIs via OATP1B3 and OCT2.

Efficacy and safety of AEZS-108 (INN: zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: a multicenter phase II trial of the ago-study group (AGO GYN 5).

OBJECTIVES: To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors. METHODS: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267mg/m(2) equimolar to 76.8mg/m(2) of free doxorubicin) every 3weeks as a two hour i.v. infusion. RESULTS: Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12weeks (95% CI: 8-20weeks), and median overall survival was 53weeks (95% CI: 39-73weeks). Toxicity profile was favorable. CONCLUSION: AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors.

Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5).

OBJECTIVE: Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone-releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients. METHODS: Patients had FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) III or IV or recurrent EC, LHRH receptor-positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors. RESULTS: From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%). CONCLUSIONS: AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor-positive EC, supporting the principle of receptor-mediated targeted chemotherapy.

Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors.

OBJECTIVES: Receptors for luteinizing hormone-releasing hormone (LHRH) can be utilized for targeted chemotherapy of cytotoxic LHRH analogs. The compound AEZS-108 (previously AN-152) consists of [D-Lys6]LHRH linked to doxorubicin. The objectives of this first study in humans with AESZ-108 were to determine the maximum tolerated dose and to characterize the dose-limiting toxicity, pharmacokinetics, preliminary efficacy, and hormonal effects. METHODS: The study included 17 women with histologically confirmed epithelial cancer of the ovary, endometrium, or breast that was metastatic or unresectable and for which standard curative or palliative measures could not be used or were no longer effective or tolerated. In each patient, immunohistochemistry of primary tumor or metastatic lesion confirmed that the tumors expressed LHRH receptors. RESULTS: One patient each received intravenous doses of 10, 20, 40, or 80 mg/m² of AEZS-108, six received 160 mg/m² and seven 267 mg/m² at 3 week intervals. Dose-limiting leukopenia and neutropenia were observed at the highest dose. A total of 6 patients, 3 patients each in both upper dose groups, showed responses to AEZS-108. The half-life of AESZ-108 was estimated to be about 2h. CONCLUSIONS: The maximum tolerated dose of AESZ-108 in the absence of supportive medication is 267 mg/m² and this dose is recommended as starting dose for therapeutic Phase II studies.

First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours.

AIM: To identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine. METHODS: Patients with solid tumours received perifosine at dosages ranging from 100-800mg/week. Eligibility criteria included life expectancy>12weeks, WHO performance status2, normal blood, liver and renal functions and no recent anticancer treatment. Drug concentrations were analysed by HPLC-MS/MS. RESULTS: Thirty six patients were recruited (75% males, mean age 54.7years, performance status 1 in 72.2%). Adverse events included nausea (69.4%), diarrhoea (55.6%), vomiting (52.8%) and abdominal pain (13.9%). Antiemetic regimens including glucocorticoids, dopamine antagonists and 5-HT3-antagonists were used as treatment and/or prophylaxis in 50% of the patients. Though MTD was formally not reached with 800mg/week, the treatment discontinuation due to diarrhoea and vomiting likely related to perifosine in two cases led to the decision to stop further dose escalation. Pharmacokinetics after a single dose were median t(max)=8.0-24.2h, median t(1/2)=81.0-115.9h and mean(geo) CL/f=0.28-0.43mL/min/kg. Urinary excretion was below 1%. Perifosine slightly accumulated and steady state was nearly reached after 2-3weeks. CONCLUSION: Oral perifosine was tolerable up to 600mg/week in cancer patients when administered with meal and prophylactic antiemetics. Based on its half-life of about 4days, a weekly regimen may be appropriate.

Luteinizing hormone-releasing hormone receptor-targeted chemotherapy using AN-152.

The luteinizing hormone-releasing hormone (LHRH; also known as gonadotropin-releasing hormone) receptor can be utilized for targeted chemotherapy with cytotoxic LHRH analogues such as AN-152, in which doxorubicin is linked to [D-Lys(6)]LHRH. Our studies demonstrate receptor-mediated actions of the cytotoxic LHRH analogue AN-152 in LHRH receptor-positive endometrial and ovarian tumors in vivo. Intravenous administration of AN-152 is far less toxic and inhibits the growth of LHRH receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin. AN-152 has no antitumor activity in LHRH receptor-negative cancers. This provides evidence for the principle of targeted cytotoxic chemotherapy to tumor cells expressing LHRH receptors. In addition, we were able to show that LHRH binding sites were only slightly reduced after AN-152 treatment. Therefore, repeated therapy is considered to be possible. The majority (80%) of human endometrial and ovarian cancers and about 50% of breast cancers express LHRH receptors. In addition, apart from reproductive organs, which are normally removed during surgical therapy, other organs and hematopoietic stem cells do not express LHRH receptors. Thus, cytotoxic LHRH analogues such as AN-152 appear to be suitable drugs for a more efficacious and less toxic targeted chemotherapy for endometrial and ovarian cancers. A recently finished phase I study assessed the dose limitations, maximum tolerated dose and pharmacokinetics of AN-152 given once every 3 weeks in patients with gynecological and breast cancers. A phase II study was started in January 2008.

Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis.

BACKGROUND: Visceral leishmaniasis (VL) is a major public health problem in Bihar, accounting for 90% of all cases in India. Development of high levels of resistance to various existing drugs necessitated the search for alternative orally administered drugs. Hospital-based studies have shown that oral miltefosine is a highly effective treatment for VL both in adults and in children. METHODS: An open, single-arm trial was designed to investigate the feasibility of treatment of VL patients with miltefosine in field conditions in 13 centers in Bihar. RESULTS: The phase 4 study was conducted among 1132 adult and pediatric VL patients. Compliance was good, with 1084 (95.5%) patients completing the full 28-day treatment course. Nine hundred and seventy-one (85.8%) patients returned for the final cure assessment at 6 months after treatment. The final cure rate was 82% by intention to treat analysis and 95% by per protocol analysis (similar to the 94% cure rate in hospitalized patients). Treatment-related adverse events of common toxicity criteria grade 3 occurred in ~3% of patients, including gastrointestinal toxicity and rise in aspertate amino transferase, alanine amino transferase, or serum creatinine levels, similar to previous clinical experience. CONCLUSION: This study supports the use of miltefosine in an outpatient setting in an area where VL is endemic.

Relapse of new world diffuse cutaneous leishmaniasis caused by Leishmania (Leishmania) mexicana after miltefosine treatment.

A 35-year-old man with a 19-year history of slowly evolving diffuse cutaneous leishmaniasis was treated with oral miltefosine, 50 mg three times a day. The patient responded after four months of miltefosine treatment with clearance of all nodular lesions and plaques from the entire body surface and had negative slit-skin smears and cultures for Leishmania. However, two months after stopping miltefosine, skin lesions reappeared and parasites were observed in samples. The relapsed lesions did not respond to an additional two-month course of miltefosine. No laboratory or clinical adverse events to miltefosine were observed. Parasites from skin lesions were cultured and identified as Leishmania (Leishmania) mexicana by isoenzyme electrophoresis.

Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours.

PURPOSE: Perifosine is an orally applicable, membrane-targeted alkylphosphocholine analogue with antitumour activity and radiosensitising properties in preclinical models. The purpose of this phase I study was to determine the feasibility and tolerability of concurrent daily perifosine and radiation in patients with advanced cancer. PATIENTS AND METHODS: Starting dose of perifosine was 50 mg/day; dose escalation was in steps of 50mg. Daily administration commenced 2 days before radiotherapy and was continued throughout the radiation treatment. At least three patients were entered at each dose level; at the 150 mg/day level 10 patients were included. Pharmacokinetic sampling was performed weekly pre-dosing. Twenty-one patients were entered. Tumour types included NSCLC (n=17), prostate, oesophageal, colon and bladder cancer. Most patients (16/21) had received prior chemotherapy; none radiotherapy. Median number of daily perifosine administrations was 31 (range 24-53). Mean radiation dose (BED(10)) was 59.8 Gy (range 50.7-87.5 Gy in 13-28 fractions). RESULTS: Major drug-related toxicities according to CTC criteria were nausea in 57%, fatigue in 48%, vomiting in 38%, diarrhoea in 38% and anorexia in 19%. No bone marrow toxicity was observed. DLT (nausea/vomiting) was encountered in two of five patients at the 200mg/day dose level. Dose-dependent steady-state plasma levels were reached after 1 week. Major radiotherapy-related acute toxicity consisted of dysphagia in 38% and pneumonitis in 29%. CONCLUSION: Perifosine can be safely combined with fractionated radiotherapy. A dosage of 150 mg/day, to be started at least 1 week prior to radiotherapy, is recommended for phase II evaluation.

Treatment of diffuse cutaneous leishmaniasis with miltefosine: a case report.

BACKGROUND: A 31-year-old man who has suffered since age 3 from diffuse cutaneous leishmaniasis (DCL), a disease with profound physical and psychosocial repercussions and no effective treatment at present, was treated with miltefosine. METHODS: The patient was treated for 120 days, 100 mg/day for 1 week, then 150 mg/day subsequently. RESULTS: Lesions were free of parasites at 43 days, and no signs of infiltration were present at day 76. No adverse side effects were observed. CONCLUSIONS: The dramatic clinical effect of miltefosine in this patient appears to fully justify further evaluation of this experimental therapy in DCL.

Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV infection.

Oral miltefosine was administered to 39 human immunodeficiency virus (HIV)-infected patients with leishmaniasis for whom standard leishmaniasis treatment had failed. Initial response was achieved in 25 patients (64%), including 16 patients (43%) with initial parasitological cure. Repeated responses after relapse and tolerability of long courses of treatment indicate the potential for development of optimized dosage schemes.

Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India.

Miltefosine has previously been shown to cure 97% of cases of visceral leishmaniasis (VL) in Indian adults. Because approximately one-half of cases of VL occur in children, we evaluated use of the adult dosage of miltefosin (2.5 mg/kg per day for 28 days) in 80 Indian children (age, 2-11 years) with parasitologically confirmed infection in an open-label clinical trial. Clinical and parasitological parameters were reassessed at the end of treatment and 6 months later. One patient died of intercurrent pneumonia on day 6. The other 79 patients demonstrated no parasites after treatment, had marked clinical improvement, and were deemed initially cured. Three patients had relapse, and 1 patient was lost to follow-up. The final cure rate was 94% for all enrolled patients and 95% for evaluable patients. Side effects included mild-to-moderate vomiting or diarrhea (each in approximately 25% of patients) and mild-to-moderate, transient elevations in the aspartate aminotransferase level during the early treatment phase (in 55%). This trial indicates that miltefosine is as effective and well tolerated in Indian children with VL as in adults and that it can be recommended as the first choice for treatment of childhood VL in India.

[Leishmaniasis--oral treatment with hexadecylphosphocholine]. / Leishmaniasis: Orale Therapie mit Hexadecylphosphocholin.

Hexadecylphosphocholine (HDPC, Miltefosine, Impavido) was synthesized at the Max-Planck-Institut für Biophysikalische Chemie in Göttingen, Germany and successfully used for the therapy of cancer metastases. At the Institute of General and Tropical Hygiene of Göttingen University the antiparasitic efficacy--earlier mentioned by Croft et al. (1987)--could be established for the first time in animals after oral administration. In India Impavido has been recently registered for the treatment of visceral leishmaniasis as the first oral medication in this indication. Clinical studies in India--actually a phase IV study is running--and Columbia (cutaneous leishmaniosis) demonstrated the excellent efficacy of this oral treatment also in patients with Antimon resistance. The cure rates are above 90% with low side effects (Impavido twice 50 mg capsules daily over 28 days).

Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis.

BACKGROUND: Miltefosine is the first oral drug with demonstrable success in treating visceral leishmaniasis in adults. Because approximately one-half of the visceral leishmaniasis patients worldwide are children, we performed a Phase I/II dose ranging study in the pediatric population in India. METHODS: Thirty-nine (39) children (defined as < 12 years of age) with visceral leishmaniasis demonstrated by parasites in splenic aspirates, were treated with oral miltefosine daily for 28 days: 21 patients received 1.5 mg/kg/day (Group A); and 18 patients received 2.5 mg/kg/day (Group B). About one-half of these children had failed prior antileishmanial treatment. RESULTS: All patients were parasitologically negative and symptomatically improved by the end of therapy on Day 28 of therapy; the initial parasitologic cure rate was 100%. Two patients in each treatment group relapsed with fever, splenomegaly and parasite-positive splenic aspirates by the end of the 6-month follow-up. The per protocol final clinical cure rate was 19 of 21 = 90% in Group A and 15 of 17 = 88% in Group B. Miltefosine was well-tolerated. As per the adult experience, gastrointestinal adverse events were seen: 33 and 39% of children experienced vomiting and 5 and 17% experienced diarrhea in Groups A and B, respectively, but all episodes were mild to moderate in severity and commonly lasted <1 day without symptomatic treatment. CONCLUSION: Oral miltefosine was safe and approximately 90% effective in this initial clinical trial of childhood visceral leishmaniasis.

Oral miltefosine for Indian visceral leishmaniasis.

BACKGROUND: There are 500,000 cases per year of visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, and all the effective agents have been parenteral. Miltefosine is an oral agent that has been shown in small numbers of patients to have a favorable therapeutic index for Indian visceral leishmaniasis. We performed a clinical trial in India comparing miltefosine with the most effective standard treatment, amphotericin B. METHODS: The study was a randomized, open-label comparison, in which 299 patients 12 years of age or older received orally administered miltefosine (50 or 100 mg [approximately 2.5 mg per kilogram of body weight] daily for 28 days) and 99 patients received intravenously administered amphotericin B (1 mg per kilogram every other day for a total of 15 injections). RESULTS: The groups were well matched in terms of age, weight, proportion with previous failure of treatment for leishmaniasis, parasitologic grade of splenic aspirate, and splenomegaly. At the end of treatment, splenic aspirates were obtained from 293 patients in the miltefosine group and 98 patients in the amphotericin B group. No parasites were identified, for an initial cure rate of 100 percent. By six months after the completion of treatment, 282 of the 299 patients in the miltefosine group (94 percent [95 percent confidence interval, 91 to 97]) and 96 of the 99 patients in the amphotericin B group (97 percent) had not had a relapse; these patients were classified as cured. Vomiting and diarrhea, generally lasting one to two days, occurred in 38 percent and 20 percent of the patients in the miltefosine group, respectively. CONCLUSIONS: Oral miltefosine is an effective and safe treatment for Indian visceral leishmaniasis. Miltefosine may be particularly advantageous because it can be administered orally. It may also be helpful in regions where parasites are resistant to current agents.