Primary objective: To determine the pharmacokinetic profile of lopinavir and ritonavir in two differ-ent co-formulations (Lopimune granules and Lopimune tablets) after single-dose in HIV-negative, healthy adult subjects, and to compare this to the…
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Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetics
Individual and mean plasma concentrations will be presented. Overlay
presentations will be given to illustrate inter-subject variability.
Descriptive statistics will be calcu-lated for the plasma concentrations at
each sampling time.
The primary comparison will be made between AUC0-inf, Tmax and Cmax values of
lopinavir and ritonavir after intake of the Reference regimen vs. after intake
of the two Test regimens. Non-parametric analysis (Wilcoxon*s signed rank test)
will be done for AUC, Cmax and Tmax values between the three different
regimens.
Secondary outcome
Demographics, Treatment Compliance, Concomitant Medication and Safety
Data on demographics, treatment compliance, concomitant medication and safety
of all subjects (including drop-outs) will be included in the clinical trial
report.
Demographics (including weight) and safety data at screening, laboratory safety
data and concomitant medication will be listed.
Descriptive statistics will be calculated for the subject characteristics.
Adverse events and serious adverse events will be listed per treatment and the
inci-dence (number of subjects with at least one AE) will be presented. Special
attention will be given to subjects who discontinued because of AEs.
Background summary
Highly Active Anti-Retroviral Therapy (HAART) has resulted in a major reduction
of morbidity and mortality of HIV-infected adults and children. HIV mortality
in children has decreased 70% since the introduction of protease inhibitor
containing combinations. Important factors in the treatment of children are the
availability of pharmacokinetic information on appropriate dosing and the
availability of appropriate drug formulations for pediatric use. The
*Guidelines for the use of antiretroviral agents in Pediatric HIV infection*
recommend to start with 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
in combination with a Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) or
a Protease Inhibitor (PI) in treatment-naïve children. The preferred PI-based
regimen consists of 2 NRTIs with lopinavir/ritonavir. The World Health
Organization recommends for the developing countries that the PI class of drugs
be reserved for second-line therapy. This is because use of PIs in an initial
treatment regimen compromises any subsequent second-line regimen. Also, the use
of PIs other then lopinavir/ritonavir and nelfinavir is more problematic in
children because of a lack of suitable pediatric formulations or a lack of
appropriate dosing information for other ritonavir-boosted PIs. Other
limitations include the requirement and the poor tolerance of ritonavir. In
2005, a tablet formulation of lopinavir/ritonavir not requiring a cold chain
(in contrast with the oral solution) became available but the tablets cannot be
split in smaller parts and the tablet has not yet been studied in children.
Still, lopinavir/ritonavir remains the preferred PI for use in children.
Another problem are the costs of antiretroviral therapy in resource-limited
countries. Fortunately, during recent years more attention has been paid to
access to care for patients in these countries. Pharmaceutical companies have
reduced drug costs through separate pricing and the G8 & United Nations have
created the Global Fund to fight global poverty-related diseases, including
HIV. Generic manufacturers have been allowed to produce HAART combinations at
much lower costs without facing patent claims.
Cipla Pharmaceuticals is a generic manufacturer residing in India that has
success-fully launched Triomune Baby, consisting of stavudine (6mg), lamivudine
(30mg) and nevirapine (50mg) and Triomune Junior, consisting of stavudine
(12mg), lamivudine (60mg) and nevirapine (100mg). These products, recently
approved by the FDA, are used as first-line therapy in children in developing
countries (FDC-Ped, Protocol ID UMCN-AKF 04.04). Cipla has now developed two
co-formulated forms of lopi-navir/ritonavir for second-line antiretroviral
therapy for children: Lopimune granules and Lopimune tablets. They contain
100mg lopinavir and 25mg ritonavir.
The pharmacokinetics and dosing requirements of the two Lopimune formulations
will be tested in a large pharmacokinetic study in HIV-infected children in
Zambia, as part of a protocol funded by the European and Developing countries
Clinical Trial Partnership (EDCTP) (see www.EDCTP.org). Before this study will
be started, information is required regarding the absorption of the two agents
from these newly developed Lopimune products. Cipla Pharmaceuticals will
conduct a formal bio-equivalence study that is required for registration
purposes as well as to meet pre-qualification criteria set by WHO.
For two reasons we think that it is desirable to have additional information on
the pharmacokinetics of these agents. First, it may take more than 6-12 months
before data will be available from the company. Second, it may be wise to
collect data inde-pendently from the manufacturer. In this way, the clinical
study in Zambia may start earlier and consequently more children may benefit
earlier from this co-formulated product.
In the main study the granules were compared to the Kaletra adult tablets. The
bioavailability of the granules was much lower compared to the tablets. It is
possible that the granules have a pharmacokinetic profile more similar to the
Kaletra oral solution, and does a food effect play a role in absorption. To
investigate whether the granules can be used in a study with children we would
like to compare the granules to the oral solution. The oral solution and
granules will be taken with food in the additional part of the study. To test
the food effect on granules, the additional study will be performed in subjects
who participated in the main study.
Study objective
Primary objective:
To determine the pharmacokinetic profile of lopinavir and ritonavir in two
differ-ent co-formulations (Lopimune granules and Lopimune tablets) after
single-dose in HIV-negative, healthy adult subjects, and to compare this to the
branded product.
Secondary objectives:
To evaluate the safety of single-dose administration of the two generic
co-formulations of lopinavir/ritonavir and compare this to the branded product.
Study design
This is a three-period, single dose, crossover, open label, comparative,
single-centre phase-I trial in 12 HIV-negative adult subjects.
Subjects will be randomly divided to one of the following sequences, so each
se-quence will be followed by two subjects
ABC; ACB; BCA; BAC; CAB; CBA
Reference regimen: Kaletra tablets (regimen A):
Lopinavir/ritonavir 200/50mg; 2 tablets
Test regimen 1: Lopimune granules (regimen B)
Lopinavir/ritonavir 100/25mg; 4 sachets with granules
Test regimen 2: Lopimune tablets (regimen C)
Lopinavir/ritonavir 100/25mg; 4 tablets
Additional part of the study (5 subjects)
DE; ED
D = Kaletra oral solution, with food
E = Lopimune granules, with food
Normal adult lopinavir/ritonavir dose
400/100mg, so 4 sachets Lopimune en 5 mL solution (80/20 mg)
9 days: 2 single doses with 1 week wash-out
Intervention
For the determination of plasma drug concentrations, blood samples of 5 mL to
obtain at least 3.0 mL of plasma will be collected in heparinized hard plastic
tubes at the following time points: 0 (predose), 0.5, 1.0, 1.5, 2.0, 3.0, 4.0,
6.0, 8.0, 24 and 32 hours post ingestion (11 samples) on Days 1, 8 and 15. The
exact times of sampling will be recorded in the case report forms.
Subjects will receive a venous catheter (with NaCl lock) for blood sampling.
Additional part: Day 1 and 8 PK days, sample sample schedule.
Study burden and risks
Healthy volunteers may suffer from side-effects associated with the intake of
studymedication. They will not directly benefit from the studyresults. When
proven that the plasmaconcentrations of lopinavir are similar after intake of
the generic formulations when compared to the branded product, a follow-up
clinical study will be initiated in HIV infected children in Zambia. These
subjects are the ones who will benefit from this study.
Geert Grooteplein 10
6500 HB Nijmegen
Nederland
Geert Grooteplein 10
6500 HB Nijmegen
Nederland
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 and not older than 55 years of age on the day of the first dosing.
2. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to the first dosing.
3. Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
4. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
5. Subject is in a good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to the first dose. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If not, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
6. Subject has a normal blood pressure and pulse rate, according to the Investiga-tor's judgement.
7. Female subject is either not of childbearing potential, defined as postmeno-pausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or is of childbearing potential and practicing one of the following methods of birth control: condoms, sponge, foams, jellies, diaphragm or copper intrauterine device (IUD); has a vasectomized partner; or total abstinence from sexual intercourse.
Exclusion criteria
1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipi-ents.
2. Positive HIV test.
3. Positive hepatitis B or C test.
4. Therapy with any drug, including oral contraceptives (for two weeks preceding dosing), except for paracetamol
5. Relevant history or presence of pulmonary disorders (especially COPD), car-diovascular disorders, neurological disorders (especially seizures and mi-graine), gastro-intestinal disorders, renal and hepatic disorders, hormonal dis-orders (especially diabetes mellitus), coagulation disorders.
6. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
7. History of or current abuse of drugs, alcohol or solvents.
8. Inability to understand the nature and extent of the trial and the procedures required.
9. Participation in a drug trial within 60 days prior to the first dose.
10. Donation of blood within 60 days prior to the first dose.
11. Febrile illness within 3 days before the first dose
12. Pregnancy or breastfeeding
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-006142-18-NL |
| CCMO | NL21709.091.08 |