Contents
- Variable Pharmacokinetics of Antiretrovirals and the Utility of Drug Level Monitoring
- The Treatment of Drug Failure: Pharmacokinetics
- What is the Role of P-glycoprotein?
- Could Exposure to Protease Inhibitors Fall over Longer Term Administration?
- Indinavir concentrations in hair correlate with HIV treatment response
- U.S. Treatment Guidelines Updated - Efavirenz Added
- U.S. FDA Approves Lamivudine for use in Hepatitis B Infection
- Lamivudine-Resistant Hepatitis B Detected in HIV-Infected Patients
- Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance
- Evidence for a Newly Discovered Cellular Anti-HIV-1 Phenotype
- Genetic Acceleration of AIDS Progression by a Promoter Variant of CCR5
- New HIV Strain Could Pose Public-Health Concerns
- New AIDS Czar Aims to Sharpen France's AIDS Effort
- UK's first interactive patient-centred medication program launched
- University of Liverpool HIV Research Group
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PHARMACOKINETICS
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Variable Pharmacokinetics of Antiretrovirals and the Utility of Drug Level Monitoring
There is now greater consensus among clinicians that reducing viral load levels to below 50 copies/mL will provide the optimum chance for long-term benefits from current anti-retroviral treatment. Recent trials, however, even in treatment na•ve patients, only successfully achieve this marker in around 50% of people (after 24 weeks of treatment) even with less strenuous regimens where compliance issues would be minimal.
Choice and potency of the drugs used are clearly not the only key to success. Just as important, are the limitations from pre-existing mutations prior to initiating or changing a regimen and whether optimum drug concentrations are reached and maintained through treatment. The increasing availability and use of resistance assays is already helping to minimise the risks from resistance and cross-resistance, but the far cheaper and convenient use of drug concentration tests is still under-utilised in the UK.
Several studies presented this year have included sub-analysis of the range of individual drug concentrations achieved, and a direct correlation with treatment response. Particularly important, because of the easy development of mutations associated with resistance, are drug concentrations of protease inhibitor and NNRTI's.
A study by Gatti, from the Universities of Genova and Verona, looked at the variability of indinavir parameters for 12 male and 4 female HIV-infected patients. Weight range was 52-90kg, age 34-45 years and BMI 17.3-26.4. Blood samples were drawn at 0.5, 1.5, 2, 3, 4, 6 and 8 hours after a steady state 800mg q8H dose and plasma concentrations were determined with an HPLC assay validated in the range 0.05-20 mg/L.
The range of the results varied significantly and extensively. Minimum concentrations for some patients exceeded the maximum concentrations of others. Cmax range 1.13 - 14.1 (mean 7,1), Cmin range nd - 1.6 (mean 0.58), AUC 1.9 - 46.0 (mean 20.3). The importance of achieving and maintaining levels within the recommended is particularly important with protease inhibitors and is emphasised by the complicated and precise dosing requirements. Developing resistance to these agents is both irreversible and limiting on long-term treatment options. (ICAAC abs. A-66).
The importance of individual drug concentration levels was also shown in the recent PACTG 382 paediatric efavirenz/nelfinavir study also presented at ICCAC (abs. LB-6, DrFax 55). Plasma concentration levels were measured at week 2 and doses adjusted for efavirenz in 20% and for nelfinavir in 8% of children. Even allowing for this, when levels were measured again at 6 weeks, 30% of children were still found to be receiving doses producing plasma levels outside of the defined therapeutic range. See also DrFax 56 for a full article from National Institute of Health on the predictive use of drug-plasma concentrations in paediatric patients using ritonavir.
In the Dutch ADAM study (primarily looking at reduction therapy), nelfinavir and saquinavir concentrations were determined in plasma at weeks 0, 1, 2, 4 and 8 by validated RP-HPLC assays. In the 30 treatment na•ve patients they found that the rate of decline of plasma HIV-1 RNA positively correlated with levels of nelfinavir exposure.
Another poster presented in Geneva [12304] found that the probability of achieving undetectable viral load (LLQ <50 copies/ml) was dependent on 2 hour post dose concentrations of nelfinavir Inter-patient differences in plasma drug concentrations in this study appeared to be of particular significance for patients with higher baseline viral load.
At present the only non-commercial UK site performing these tests is the University of Liverpool but Professor David Back routinely offers this service to any other treatment centre. He currently provides tests for all approved protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), and NNRTI's (delavirdine, nevirapine). Plasma samples need to be drawn at different times depending on the individual drug and dosing schedule, and need to be spun in a lithium heparin tube, stored at -20ˇC and delivered on dry ice. Aside from this preparation and delivery, tests cost Ł25 per patient per drug.
Take-up of this facility within the UK has been extremely limited in spite of the cost and health benefits for patients starting or changing to either protease or NNRTI therapy. It can also be important in assessing why a particular combination may not be achieving the necessary potency when previous drug history and adherence indicate it should have been an effective choice. An early example of the value of these tests was with the earlier formulation of saquinavir (Invirase). Concerns over the poor bioavailability of this drug encouraged Dr Peter Carey at City of Liverpool hospital to monitor all patients using this drug. On doing this it was found that over 30% of patients registered no measurable levels of saquinavir.
Dr Ceppie Merry, at St James' Hospital, Dublin, routinely tests every patient who is able to attend the day ward for the few hours involved (and creates a database of results as a guide for those patients who cannot attend, because of work or childcare commitments). Dr Merry has outlined several particularly important uses:
- Confirming effective doses for all patients who start an PI or NNRTI including combination
- Establishing effective dosing levels for patients on combinations which include two PI's, or a PI and NNRTI, where drug interactions are known to be a complicating factor
- Monitoring patients with cirrhosis or other pre-existing liver conditions, in order to safely manage dose reductions (of protease inhibitors) without risking suboptimal dosing
- Responding to patient demand for safety information for other new and experimental drugs. A recent example includes Viagra which patients have been able to use since its approval in the US. This also includes monitoring safety profiles on an individual level for patients using methadone.
- Offering patients alternative dosing options. For example, patients who have difficulties with side-effects 2 hours after taking ritonavir on a BID regimen and who are know to be adherent, have been able to safely use a reduced dose four times a day, which is far easier to tolerate;
The minimal costs are emphasised by Dr Graham Taylor, at St Mary's Hospital, Paddington, who uses the tests within his family clinic to be certain that women using combination therapy through their pregnancy are receiving safe doses of nevirapine or a protease inhibitor where they form part of the treatment.
Dr Mark Nelson, at the Chelsea & Westminster Hospital, London, recently completed a study looking at the safety of BID indinavir dosing, in addition to now using ultrasensitive viral load tests, he aims to measure indinavir drug concentration levels in all patents. Although Merck have recommended everyone should now return to a TID regimen, having closed their trials early (DrFax 55), many patients who switched to the simpler regimen have continued to remain below detection, have not experienced viral rebound and may be reluctant (or unwilling) to return to the TID schedule.
PK studies indicated possible risks from lower trough levels at the BID dose, although the TID schedule can cause adherence difficulties. Individual testing in this (and other reduced dosing situations) will provide both clinicians and patients with a stronger scientific basis for the safety of either regimen.
Author: Simon Collins, ATP.
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David Back can be contacted at Liverpool University on 0151 794 5547. Drug monitoring facilities are also planned at the Chelsea & Westminster Hospital, London. |
The Treatment of Drug Failure: Pharmacokinetics Author: Steven Deeks, M.D.
Source: Clinical Care Options for HIV, http://www.healthcg.com/hiv/
What is the Role of P-glycoprotein?
Author: Ian G. Williams, F.R.C.P. Source: Clinical Care Options for HIV, http://www.healthcg.com/hiv/
Could Exposure to Protease Inhibitors Fall over Longer Term Administration?
Khaliq and colleagues from Ottawa Hospital presented a thought provoking study at the recent meeting in Glasgow [abstract P-43]. The study examined the multiple dose pharmacokinetics (PK) of saquinavir hard gel capsule (SQV-hgc) administered concurrently with nelfinavir (NFV) in both TID and BID regimens over both the short and longer term.
As expected coadministration of NFV increased substantially the total and peak exposure to saquinavir in line with previous pharmacokinetic interaction studies. When the short-term administration PK was compared to the longer term PK, however, it was found that the exposure to both SQV-hgc and NFV had decreased over time.
In the TID arm (n=5) after 7-12 months of coadministration, total and peak SQV exposure significantly decreased by 56% (AUC) and 54% (Cmax), p<0.017). SQV predose levels (C8) significantly decreased from 228(83 to 73(29 ng/mL (p=0.0001). The BID arm (n=6) also experienced decreases in SQV exposure after 4-8 months of coadministration. Total and peak SQV exposure in this group decreased by 43% and saquinavir predose levels decreased from 219(80 to 131(59 ng/mL. The decreases observed over time in this BID arm failed to reach significance. It should be noted, however, that the timepoint of the sampling for the longer-term administration (4-8 months) was considerably shorter than that of the TID arm (7-12 months).
In both the BID and TID groups mean NFV AUC and Cmax values decreased non-significantly with longer term treatment (AUC -37% TID, -21% BID. Cmax -23% TID, -20% BID).
The investigators conclude by speculating that the observed decrease in SQV exposure with longer-term administration of these protease inhibitors may be due to upregulation of CYP3A4 or p-glycoprotein, slow autoinduction or in the case of the SQV, to the falling NFV exposure.
Author: Paul Blanchard, ATP.
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Individual variabilities amongst individuals in expression of the MDR1 gene may partially explain wide variability of PK seen with both PI's and NNRTI's. Variable expression in different cell lines and in tissue barriers may also explain variable penetration into body compartments and cell types. Changes in the pharmacokinetics with long term administration are thought possible for all protease inhibitors. Indeed, warnings about this possibility is included in the saquinavir-sgc (Fortovase) U.S. package insert. Falling plasma levels of PI's with continued administration may perhaps, explain the loss of virologic control seen over time in a significant number of people who have had previously successful suppression of HIV-replication using combinations containing these agents. Ritonavir co-therapy, as a potent cytochrome p450 and P-gp inhibitor may have a particular role to play in guarding against degradation of drug levels over time. The implications of decreasing exposure over time serve to underline the importance of regular and continued drug level monitoring and individual dose titration. This is already common practice with other pharmaceutical agents such as lithium and thyroxine and should now be given serious consideration in the treatment of HIV-disease. As the necessity of long-term administration of these agents is also becoming patently clear, it should also be a requirement for regulatory approval that the pharmacokinetics are checked for stability over such long-term administration. |
Indinavir concentrations in hair correlate with HIV treatment response.
An original method to evaluate protease inhibitor absorption by HIV-positive patients, or to evaluate patient adherence to treatment, is proposed by French researchers, who have used patient hair samples to determine drug concentrations.
A study of 30 patients who received triple combination antiretroviral therapy that included the protease inhibitor indinavir was presented at the 18th Interdisciplinary Meeting of Anti-Infectious Chemotherapy (RICAI) in Paris by researchers from the Hopitaux Raymond Poincare a Garches et Bichat in Paris and INSERM U472.
The researchers attempted to correlate protease inhibitor concentrations in hair samples with drug exposure levels and with response to treatment. Among the 30 patients, 19 responded to treatment, as indicated by undetectable viral load of less than 50 copies/mL, and 11 did not respond to treatment.
They found that the quantity of indinavir in hair samples to be greater among responders than among the nonresponders, regardless of the segment of hair analysed. There was also a correlation over time between an increase in viral load and a decrease in indinavir concentrations in the hair, and vice versa.
However, three nonresponders had high concentrations of indinavir in their hair, which suggested that the plasma drug concentrations were also high. Virological analysis of these subjects revealed several mutations indicating the emergence of HIV resistance.
The researchers conclude that measuring protease inhibitor concentrations in the hair, in addition to the traditional methods of follow-up, could improve detection of patients with subtherapeutic drug levels, due to poor treatment adherence or poor drug absorption. This test may also help physicians identify the reason why some HIV-positive patients do not respond to treatment.
Source: CDC HIV/STD/TB Prevention News Update
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Hair analysis may provide a useful "archival" measure of total drug exposure overtime. However, it's use in therapeutic drug level monitoring is likely to be limited. |
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ANTIVIRALS
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U.S. Treatment Guidelines Updated - Efavirenz Added
The HIV/AIDS Treatment Information Service announces that The Panel on Clinical Practices for Treatment of HIV Infection has updated the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. This update includes information about the most recently approved HIV drug, Efavirenz. Additional information regarding class adverse events and adherence are included as supplemental links from the guidelines.
Efavirenz (Sustiva), which received U.S. Food and Drug Administration approval nearly three months ago, has been included in the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. A U.S. Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection has advised that the drug be listed in column A, which lists antiviral therapies for treating established HIV infection. Efavirenz is the first non-nucleoside reverse transcriptase inhibitor to become a "preferred agent."
The Guidelines are available in Portable Document Format (pdf) through the HIV/AIDS Treatment Information Service Web site at:
and from the National Prevention Information Network at:
They are also available as an easy to access html document courtesy of Healthcare Communications Group:
http://www.healthcg.com/hiv/nihreport/guide/
U.S. FDA Approves Lamivudine for use in Hepatitis B Infection
The Food and Drug Administration has approved the use of lamivudine, also known as 3TC, to help protect against the liver damage caused by chronic hepatitis B virus infection. Lamivudine, which has already been approved for use against HIV, blocks the production of an enzyme that is used by both viruses. Glaxo Wellcome, the manufacturer of the drug, will sell a special lower-dose version of the medication for use against hepatitis B under the name Epivir HBV, costing half as much as the higher-dose HIV treatment.
Source: Washington Post (12/10/98) P. A42
Lamivudine-Resistant Hepatitis B Detected in HIV-Infected Patients
French researchers report the discovery of lamivudine resistance among 19 patients co-infected with hepatitis B virus (HBV) and HIV. In four subjects who showed re-emergence of HBV DNA after reaching undetectable levels, polymerase chain reaction analysis showed evidence of HBV mutations. Lamivudine was recently approved by the US Food and Drug Administration as the first oral therapy for chronic HBV infection.
"This emergence [of resistance] was well tolerated clinically," reported researchers from the l'Hotel-Dieu de Nantes, who presented their results at the 18th Interdisciplinary Meeting of Anti-Infectious Chemotherapy (RICAI) in Paris. Nevertheless, "...their long-term pathogenicity remains hypothetical." Dr. FranŤois Raffi and colleagues described the follow-up of a group of 19 patients coinfected with HIV and HBV who were treated with lamivudine within the framework of triple antiretroviral therapy, which included a protease inhibitor for 12 subjects. Six of these patients had already failed hepatitis B treatment with interferon. HBV DNA was initially detected in 17 patients. It became undetectable in 13 patients after an average of 3.8 months of treatment but re-emerged in 6 of these 13 patients. In 2 of these 6 subjects, re-emergence of HBV DNA was associated with interruption of treatment. But in the other 4 subjects, the results of polymerase chain reaction analysis indicated evidence of HBV mutations. Dr. Raffi's group also pointed out that the duration of lamivudine treatment was longer among patients with evidence of HBV mutations-19.3 months vs 8.8 months among the other patients.
Source: CDC HIV/STD/TB Prevention News Update
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In many ways it is extraordinary that monotherapy approaches in other viral illnesses are expected to succeed after their dramatic failures in the setting of HIV. It is likely that combination therapy for HBV infection will be the necessary next step (eg. Famvir, 3TC, ribavirin +/- interferon-alpha). |
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PATHOGENESIS
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Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance
A team of Harvard University researchers discovered the structure of HIV-1 reverse transcriptase (RT) while covalently trapped in a complex with a DNA template:primer and a deoxynuclease triphosphate (dNTP). HIV-1 RT is composed of two chains with four common domains, referred to as "fingers," "palm," "thumb," and "connection." There were conformational changes associated with the binding of the template:primer and dNTP, with the outer part of the finger domain bringing the "fingertips" closer to the palm, which in turn moves toward the core. The researchers note that two broad conclusions can be drawn from the structure: point mutations that are sufficient for resistance are all in the neighbourhood of the incoming nucleotide and that the mutation sites which confer resistance to the dideoxy class of RT inhibitors all impinge on the "front," while AZT resistance mutation sites impinge on the 3'-carbon pocket from the "rear." A multinucleotide resistance mutation at position 151 lies in the middle of these positions, directly across the bound dNTP. The authors conclude that "the clustering of mutations correlates well with cross resistance."
Ref: Science (27/11/98) Vol. 282, No. 5394, P. 1669; Huang, Huifang; Chopra, Rajiv; Verdine, Gregory L.; et al. Source: CDC HIV/STD/TB Prevention News Update
Evidence for a Newly Discovered Cellular Anti-HIV-1 Phenotype
Researchers investigated the function of the HIV-1 virion infectivity factor (Vif), finding that the protein appears to counteract a newly discovered activity in human cells that otherwise inhibits virus activity. They analysed HIV-infectivity in cells that support the replication of Vif-deficient HIV-1 (permissive cells) and in cells that do not allow Vif-deleterious HIV to replicate (non-permissive cells). They observed that Vif increased virus infectivity 10 to 20 times in experimental conditions when the viruses were produced either by unfused non-permissive cells or by non-permissive cells fused to permissive cells. According to the authors, "our findings are most consistent with the idea that non-permissive human T-cells have an activity whose expression presence results in the inhibition of HIV-1 infectivity, and that the function of Vif is to counteract this." They speculate that Vif modulates the assembly, budding, and/or maturation life cycle stages of the virus. Vif may represent a useful target for future HIV-1 therapies, since blocking Vif function should allow the naturally putative antiviral activity of T cells to become operative.
Ref: Nature Medicine (12/98) Vol. 4, No. 12, P. 1397; Simon, James H.M.; Gaddis, Nathan C.; Fouchier, Ron A.M.; et al. Source: CDC HIV/STD/TB Prevention News Update
Genetic Acceleration of AIDS Progression by a Promoter Variant of CCR5
Researchers, led by Maureen P. Martin of the National Cancer Institute, report that individuals homozygous for a multisite haplotype of the CCR5 regulatory region with the CCR5P1 promoter allele progress to AIDS faster than individuals with other promoter genotypes. The researchers examined CCR5 promoter genotypes among more than 2,600 individuals and found that an estimated 10 percent to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection doing so because they are homozygous for CCR5P1/P1. Additionally, the patients seemed to progress faster particularly during the early stages of infection. About 12.7 percent of Caucasians and 6.7 percent of African-Americans carry a CCR5P1/CCR5P1 genotype. According to the researchers, the findings could aid in the development of new treatments.
Ref: Science (04/12/98) Vol. 282, No. 5395, P. 1907; Martin, Maureen P.; Dean, Michael; Smith, Michael W.; et al. Source: CDC HIV/STD/TB Prevention News Update
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OTHER
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New HIV Strain Could Pose Public-Health Concerns
A new HIV strain detected in a woman in Cameroon may not immediately affect public health, but it may provide some insight into the origin of the disease. The new strain, dubbed "YBF 30" or HIV-1 group N, is distinct from group M (the major HIV group) and group O HIV strains. Dr. Harold W. Jaffe, associate director for HIV/AIDS in the National Center for Infectious Diseases at the Centers for Disease Control and Prevention, explained that the new group is interesting from an academic standpoint because it indicates that the disease may have originated from non-human primates. He noted, though, that there may be some concerns as to whether current HIV tests at blood banks can detect the new strain. Some tests can detect group O, but further studies are needed to determine if screening tests recognise group N. The Food and Drug Administration currently requires all newly licensed tests for blood banks to be able to screen for the group O strain. Jaffe added, however, that "on the group N, we just don't have any information at all. It's probably appropriate to be concerned to the extent of looking at how well our tests detect these variants." Questions relating to whether current viral-load tests are reliable for group N exist as well, but this issue less of a public health concern and more of a problem in individual patient treatment, Jaffe said.
Source: CDC HIV/STD/TB Prevention News Update Ref: AIDS Alert (11/98) Vol. 13, No. 11, P. 126
New AIDS Czar Aims to Sharpen France's AIDS Effort
With the appointment of France's new AIDS czar, Michel Kazatchkine, the National Agency for AIDS Research (ANRS) will narrow its research focus to studies designed to lead to new therapies. Kazatchkine replaced Jean-Paul Levy as the head of the French agency in October amid rumours that ANRS would be disbanded after Levy stepped down. The agency has a mandate through 2000, at which time the French government will decide whether to renew it. Kazatchkine said that "basic [AIDS] research should not just bring one more piece of the puzzle but have the goal of identifying new targets for therapy." About one-quarter of the agency's $42 million budget for 1999 will be spent on basic research, but half of the money will be reserved for projects meant to foster new therapies. The budget for vaccine research will increase 18 percent from about $6.4 million in 1998.
Ref: Science (04/12/98) Vol. 282, No. 5395, P. 1799; Balter, Michael Source: CDC HIV/STD/TB Prevention News Update
UK's first interactive patient-centred medication program launched
A new patient-centred interactive computer program designed to help AIDS pharmacists and clinicians involved in planning HIV/AIDS therapy has been launched in the U.K. The program, developed by the AIDS Pharmacists Group in partnership with Boehringer Ingelheim, allows the patient and pharmacist to 'build' a personal medication plan around the individual's daily routine and preference.
The program provides an opportunity for the pharmacist and patient to work through each medication and see how the timing of doses dietary restrictions and potential interactions with the timing of other drugs can be accommodated into the individual's day. Once a workable regimen has been agreed, the patient is provided with a printed medication plan. If required, the pharmacist can maintain an anonymous, computerised, record of the patients therapy to assist with clinic based audits.
"Many patients may be prescribed more than 20 tablets each day covering antiretroviral therapies and prophylaxis and treatment of opportunistic infections. How these regimens are scheduled is vital to promote compliance and improve the patient's quality of life. This program has been developed to give the patient the chance to take part in the process allowing them to make choices with their therapy advisor", commented Rosy Weston of the steering committee of the AIDS Pharmacists' Group.
The software program offers many features:
- Interactive: it allows patients to participate in the planning of their dug regimens.
- Drug notifications: All important drug requirements and dosing restrictions are automatically highlighted
- Interactions: All temporal interactions between commonly used drugs are highlighted automatically (specific drug:drug interactions are not included in this database).
- Drug database: Supplied with a drug database which can be easily adapted by the Pharmacist to incorporate additional drugs for example those available as part of expanded access programmes and study medications.
- Regular Updates: Users will be provided with quarterly updates to the drug database following major scientific conferences.
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Copies of the program are available free of charge by contacting Janine Saunders at Boehringer Ingelheim on 01344 741162. |
University of Liverpool HIV Research Group
Based in the Department of Pharmacology & Therapeutics at the University of Liverpool, the group is involved in the study of the clinical pharmacology of anti-HIV drugs, combining basic research with clinical studies.
The group is currently involved in laboratory research into the activation of the nucleoside analogues and the disposition of the protease inhibitors and the non-nucleoside analogues. In addition to research there is also a commitment to providing information for patients and physicians relating to potential drug interactions and a therapeutic drug monitoring service.
Laboratory Services
Routine assays for measuring plasma (serum) concentrations of:
Nucleoside Analogues (by radioimmunoassay)
- Zidovudine (ZDV/AZT)
- Didanosine (ddI)
- Zalcitabine (ddC)
- Ritonavir
- Saquinavir
- Indinavir
- Nelfinavir
- Nevirapine
Other Drugs
- Methadone
Measurement of intracellular zidovudine phosphorylated metabolites:
- cell separation facilities available
- samples assayed by HPLC & RIA
- ultra sensitive assay in development for ZDV and 3TC triphosphate
Other Pharmacology Services
- Metabolic studies of licensed drugs or drugs in development:
- Determination of metabolic profiles using human liver microsomes and isolated enzymes (GENTEST cell lines).
- Characterisation by HPLC, LCMS, NMR etc.
- Determination of potential inhibition effects on cytochrome P450 isozymes.
- Determination of the role of transport proteins in drug dispostion.
- Antiviral studies in chronically and acutely infected cells.
- Drugs tested alone and in combination
Drug Interaction Charts
Protease Inhibitor Drug Interactions Updated December 1998 Website charts have been compiled to provide a summary of drug interactions between protease inhibitors and other drugs that may be prescribed to the HIV-infected patient as well as how one anti-HIV drug may affect the pharmacokinetics (and activation by phosphorylation, if applicable) of another when given in combination.
These authoritative drug interaction charts which are comprehensive and extremely well referenced can be accessed at: