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Biomedical subjects

John G Gerber

Publications and source records attributed to John G Gerber.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacodynamics of antiretroviral agents in HIV-1 infected patients: using viral dynamic models that incorporate drug susceptibility and adherence.

We developed a novel HIV-1 dynamic model with consideration of pharmacokinetics, drug adherence and drug susceptibility to link plasma drug concentration to the long-term changes in HIV-1 RNA observation after initiation of therapy. A Bayesian approach is proposed to fit this model to clinical data from ACTG A5055, a study of two dosage regimens of indinavir (IDV) with ritonavir (RTV) in subjects failing their first protease inhibitor treatment. The HIV RNA testing was completed at days 0, 7, 14, 28, 56, 84, 112, 140, and 168. An intensive pharmacokinetic (PK) evaluation was performed on day 14 and multiple trough concentrations were subsequently collected. Pill counts were used to monitor adherence. IC(50) for IDV and RTV were determined at baseline and at virologic failure. Viral dynamic model fitting residuals were used to assess the significance of covariate effects on long-term virologic response. As univariate predictors, none of the four PK parameters C(trough), C(12 hour), C(max), and AUC was significantly related to virologic response (p > 0.05). By including drug susceptibility (IC(50)), or IC(50) and adherence measured by pill counts together, C(trough), C(12 hour), C(max) and AUC were each significantly correlated to long-term virologic response (p = 0.0055,0.0002,0.0136,0.0002 with IC(50) and adherence measured by pill counts considered). The IC(50) and adherence measured by pill counts alone were not related to the virologic response. In predicting virologic response adherence measured by pill counts did not provide any additional information to PK parameters (p = 0.064), to drug susceptibility IC(50) (p = 0.086), and to their combination (p = 0.22). Simple regression approaches did not detect any significant pharmacodynamic (PD) relationships. Any single factor of PK, adherence measured by pill counts and drug susceptibility did not contribute to long-term virologic response. But their combinations in viral dynamic modeling significantly predicted virologic response. The HIV dynamic modeling can appropriately capture complicated nonlinear relationships and interactions among multiple covariates.

Algorithms↗
PubMed2006

Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108.

BACKGROUND: Nelfinavir, an HIV protease inhibitor with numerous drug-drug interactions, is associated with dyslipidemia. Pravastatin is the preferred statin prescribed for HIV-associated dyslipidemia. OBJECTIVE: To examine the effect of nelfinavir on pravastatin pharmacokinetics. DESIGN: Open-label study in healthy HIV-seronegative adults conducted at the AIDS Clinical Trials Group sites in the United States. METHODS: Subjects received pravastatin 40 mg daily and underwent intensive sampling for pharmacokinetics on day 3. Subjects took only nelfinavir 1250 mg twice daily on days 4-12. On days 13-15, subjects continued nelfinavir and reinitiated pravastatin. Plasma samples were collected over 24 h for the calculation of pravastatin area under the concentration-time curve for 0-24 h on days 3 and 16. RESULTS: Data from 14 subjects with complete pharmacokinetic samples were available for analysis. The median within-subject percentage change in pravastatin AUC was a decrease of 46.5%. Pravastatin maximum plasma concentrations were also lower when pravastatin was administered with nelfinavir. Median values for the maximum plasma concentrations were 27.9 and 12.4 ng/ml for days 3 and 16, respectively, and the median within-subject decrease was 40.1%. CONCLUSIONS: Coadministration of pravastatin and nelfinavir led to a substantial reduction in pravastatin plasma concentrations. Higher doses of pravastatin may need to be prescribed in order to achieve optimal lipid-lowering activity.

Adult↗
PubMed2006

Amdoxovir versus placebo with enfuvirtide plus optimized background therapy for HIV-1-infected subjects failing current therapy (AACTG A5118).

BACKGROUND: Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses. METHODS: ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade > or = 3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks. RESULTS: Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI = -2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI = -1.1, -0.1) in the placebo arm (P = 0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI =1, 115) in the DAPD arm and 60 (95% CI =1, 101) in the placebo arm (P = 0.45). Time to first serious AE did not differ between arms (P = 0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities. CONCLUSIONS: Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.

Adult↗
PubMed2005

The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing.

The trend toward once-daily dosing in HIV antiretroviral therapy is based on the association between adherence, treatment outcome, and patient preferences. Patients prefer simpler treatments, fewer pills, less frequent dosing, and no food restrictions. When a regimen meets a patient's preferences, the patient is more likely to be adherent, and with good adherence, the regimen is more likely to be effective. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been a prime focus for developing once-daily therapies primarily because they form the backbone of most current regimens. Within the NRTI class, however, drugs differ in their pharmacokinetic properties, such as plasma and intracellular half-lives, and thus in their suitability for once-daily dosing. For example, newer NRTIs, such as tenofovir and emtricitabine, combine longer plasma half-lives with longer intracellular half-lives, prolonging exposure and the period of pharmacologic activity. Of equal importance, the clinical impact of systemic and intracellular interactions between concomitant drugs defines which once-daily drugs may be combined in once-daily regimens. To construct simplified and effective therapies for individual patients, clinicians require an understanding of the plasma and intracellular pharmacokinetic properties of NRTIs and how these properties determine a drug's appropriateness for once-daily dosing and placement within a once-daily regimen.

Drug Administration Schedule↗
PubMed2005

Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy.

OBJECTIVE: To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations. DESIGN: The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults. METHODS: Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection. RESULTS: Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008). CONCLUSIONS: The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.

Adult↗
PubMed2005

Modeling long-term HIV dynamics and antiretroviral response: effects of drug potency, pharmacokinetics, adherence, and drug resistance.

We propose a long-term HIV-1 dynamic model by considering drug potency, drug exposure, and drug susceptibility. Using a Bayesian approach, HIV-1 dynamic parameters were estimated by fitting the model to viral load data from a phase 1/2 randomized clinical study of 2 indinavir (IDV)/ritonavir (RTV)-containing highly active antiretroviral (ARV) therapy regimens in HIV-infected subjects who had previously failed protease inhibitor-containing ARV therapies. A large between-subject variation in estimated viral dynamic parameters was observed, even after accounting for variations in drug exposure and drug susceptibility, suggesting that characteristics of HIV-1 dynamics are host dependent. Significant correlations of baseline factors such as HIV-1 RNA levels and CD4 cell counts with viral dynamic parameters were found. These correlations coincide with biologic interaction mechanisms between HIV and the host immune system and also provide an explanation for the correlations between the baseline viral load and phase 1 viral decay rate, for which inconsistent results have been reported in the literature. The relations between viral dynamic parameters and virologic response were established, and these results suggest that viral dynamic parameters may play an important role in determining treatment success or failure. In particular, we estimated a drug efficacy threshold for each patient that can be used to assess whether an ARV regimen is potent enough to suppress HIV viruses in the individual patient. Our findings indicate that it is necessary to individualize the ARV regimen to treat HIV-1-infected patients. The proposed mathematic models and statistical techniques may provide a framework to simulate and predict antiviral response for individual patients.

Anti-HIV Agents↗
PubMed2005

Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study.

Efavirenz (EFV) is associated with hyperlipidemia when used in combination with other antiretroviral drugs. EFV is a mixed inducer/inhibitor of cytochrome P450 (CYP) 3A4 isozyme and may interact with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are primarily metabolized via CYP3A4. To assess the drug-drug interaction of EFV used in combination with simvastatin (SIM), atorvastatin (ATR), or pravastatin (PRA), an open-label trial was conducted in 52 healthy adult HIV-seronegative subjects across AIDS Clinical Trials Group sites in the United States. Subjects received 40 mg of SIM, 10 mg of ATR, or 40 mg of PRA daily on days 0 through 3 and days 15 through 18. EFV was administered daily at a dose of 600 mg on days 4 through 18. SIM, ATR, and PRA concentrations were determined before and after EFV, and EFV concentrations were determined before and after statins. EFV reduced SIM acid exposure (area under the curve at 0 to 24 hours [AUC0-24 h]) by 58% (Wilcoxon signed rank test, P=0.003) and active HMG-CoA reductase inhibitory activity by 60% (P<0.001). EFV reduced ATR exposure by 43% (P<0.001) and the total active ATR exposure by 34% (P=0.005). EFV administration resulted in a 40% decrease in PRA exposure (P=0.005). SIM, ATR, and PRA had no effect on non-steady-state EFV concentrations. In conclusion, EFV, when administered with SIM, ATR, or PRA, can result in significant induction of statin metabolism. The reduced inhibition of HMG-CoA reductase activity during coadministration of EFV may result in diminished antilipid efficacy at usual doses of SIM, ATR, and PRA.

Adult↗
PubMed2005

Determination of the absolute configuration and solution conformation of the antifungal agents ketoconazole, itraconazole, and miconazole with vibrational circular dichroism.

The absolute configuration assignments of three antifungal agents, (+)-(2R,4S)-ketoconazole, (+)-(2R,4S)-itraconazole (with (S)-configuration at the sec-butyl group) and (+)-(S)-miconazole nitrate have been confirmed by using vibrational circular dichroism (VCD). For these three antifungal drugs, this study also provides evidence for the most abundant conformations of miconazole and for the relative conformations of the azole, dichlorophenyl, and methoxyphenyl groups in ketoconazole and itraconazole, in chloroform solution.

Antifungal Agents↗
PubMed2005

Therapeutic drug monitoring: pharmacologic considerations for antiretroviral drugs.

Therapeutic drug monitoring (TDM) is the process by which a patient's dosing regimen is guided by repeated measures of plasma drug concentrations. An enormous challenge with regard to TDM of antiretroviral drugs (ARV) is that the concentration goals can be moving targets. Well-designed prospective studies demonstrating that prospectively altering ARV doses based on TDM leads to virologic success and increased tolerability are needed. Nevertheless, there are specific clinical instances where this experimental intervention should be considered to potentially reduce toxicity and improve therapeutic outcomes.

Adolescent↗
PubMed2005

Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers.

BACKGROUND: Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir. METHODS: Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days 1 to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19. RESULTS: Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng.h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng.h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed. CONCLUSIONS: Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects.

Adolescent↗
PubMed2004

Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction.

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Alkynes↗
PubMed2004

Comparison of two indinavir/ritonavir regimens in the treatment of HIV-infected individuals.

BACKGROUND: Pharmacokinetic enhancement of protease inhibitors (PIs) with low-dose ritonavir (RTV) for salvage therapy is increasingly common. The purpose of this study was to compare the pharmacokinetics, safety, and tolerability of indinavir (IDV)/RTV at 800/200 mg (arm A) and 400/400 mg (arm B) administered twice daily in HIV-infected subjects failing their first PI-based regimen. METHODS: A phase I/II, randomized, open-label, 24-week study was conducted. Formal 12-hour pharmacokinetic evaluations were performed, and study visits occurred at baseline; at weeks 1, 2, and 4; and every 4 week thereafter for 24 weeks. Clinical symptoms and laboratory assessments were collected. Subjects were allowed to switch arms because of toxicity. RESULTS: Forty-four subjects were enrolled (22 per arm). IDV predose concentration, maximum plasma concentration and area under the curve were significantly higher in arm A. Fifty-five percent and 45% of subjects in arms A and B responded (<200 copies/mL at week 24; P = 0.76), respectively. CD4 cell responses were similar. All subjects had IDV-sensitive virus at baseline and at virologic failure. Tolerability was comparable, but all grade 3 or higher triglyceride increases occurred in arm B and more subjects in arm B switched because of toxicity (5 vs. 1 triglyceride increases). CONCLUSIONS: This is the largest formal pharmacokinetic evaluation of 2 dosage combinations of IDV/RTV in HIV-infected individuals. Pharmacokinetic parameters were consistent with previous results in patients but lower than in seronegative controls. Both regimens exhibited similar tolerability and response rates. High toxicity with a low response suggests that the optimum IDV/RTV combination would include an RTV dose <400 mg and an IDV dose <800 mg in this population.

Adolescent↗
PubMed2004

Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates.

Racemic ketoconazole (KTZ) was the first orally active azole antifungal agent used in clinical practice and has become widely used in the treatment of mucosal fungal infections associated with AIDS immunosuppression and cancer chemotherapy. However, the use of KTZ has been limited because of adverse drug-drug interactions. KTZ blocks ergosterol biosynthesis by inhibiting the fungal cytochrome P450 (CYP51). KTZ is also a potent inhibitor of human cytochrome P450 3A4 (CYP3A4) enzyme, the major drug-metabolizing CYP isozyme in the human liver. We examined the enantioselective differences of KTZ in the inhibition of human CYP3A4 and in antifungal action. Dextro- and levo-KTZ exhibited modest enantioselective differences with respect to CYP3A4 inhibition of testosterone and methadone metabolism. For both substrates levo-KTZ was approximately a 2-fold more potent inhibitor. We examined the enantioselective differences in the in vitro activity of KTZ against medically relevant species of Candida and Aspergillus, as well as Cryptococcus neoformans. Overall, levo-KTZ was 2-4-fold more active than dextro-KTZ. Therefore, levo-KTZ is a more potent inhibitor of CYP3A4 and has stronger in vitro antifungal activity. Chirality 16:79-85, 2004.

Antifungal Agents↗
PubMed2004

Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19.

Methadone is a clinically used opioid agonist that is oxidatively metabolized by cytochrome P450 (CYP) isoforms to a stable metabolite, EDDP. Methadone is a chiral drug administered as the racemic mixture of (R)-(-)- and (S)-(+)-methadone, but (R)-methadone is the active isomer. The cytochrome P450 (CYP) isoform involved in methadone's metabolism is thought to be CYP3A4, but human drug-drug interaction studies are not consistent with this. The ability of the common human drug-metabolizing CYPs (obtained from baculovirus-infected insect cell supersomes) to generate 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrilidine (EDDP) from racemic methadone was examined and then determined if the CYP isoforms metabolized methadone stereoselectively. Only CYP2B6, 2C19, and 3A4 generated measurable EDDP from 1 microg/ml of racemic methadone. The hierarchy of EDDP generation was CYP2B6 > CYP2C19 >/= CYP3A4. At 10 microg/ml of methadone, CYP2C9 and CYP2D6 also generated EDDP, but in at least 10-fold lower quantities than CYP2B6. Michaelis-Menten kinetic data demonstrated that CYP2B6 had the highest V(max) (44 ng/min/10pmol) and the lowest K(m) (12.6 microg/ml) for EDDP formation of all the CYP isoforms. In human liver microsomes with high and low CYP2B6 expression but equivalent CYP3A4 expression, high CYP2B6 expression microsomes generated twice the amount of EDDP from 10 microg/ml of methadone than low CYP2B6 expression microsomes. When stereoselective metabolism of racemic methadone by CYP2B6, 2C19, and 3A4 was examined using an enantiospecific methadone assay, CYP2B6 preferentially metabolized (S)-methadone, CYP2C19 preferentially metabolized (R)-methadone, and CYP3A4 showed no preference. These data suggest that multiple CYPs metabolized methadone but CYP2B6 had the highest V(max)/K(m). In addition, only CYP2B6 and 2C19 showed stereoselective metabolism. Our data could explain why the plasma concentration ratio of R/S methadone is variable and why drugs that induce CYP2B6 such as nevirapine and efavirenz also induce methadone metabolism, while the CYP3A4 inducer rifabutin has no effect on methadone pharmacokinetics.

Analgesics, Opioid↗
PubMed2003

Therapeutic drug monitoring in the treatment of HIV-infection.

The use of therapeutic drug monitoring (TDM) in the treatment of HIV-infection is gaining momentum in resource-rich countries. However, data justifying its use is still in short supply. In this manuscript we review the necessary components of TDM before it should be implemented in widespread clinical use. In addition, we provide specific examples of clinical situations where TDM is likely to useful. The overall conclusion of this review is that TDM is a promising therapeutic modality for improving antiretroviral efficacy and reducing toxicity. However, more prospective clinical trials are necessary in order to validate the therapeutic concentrations of antiretroviral drugs suggested by various investigators. In addition, both the clinical utility and cost effectiveness of TDM will need to be demonstrated by well-designed and adequately powered clinical trials in both antiretroviral nai;ve and experienced subjects. At this point in time we consider TDM in the treatment of HIV-infection as experimental with significant promise for the future.

Anti-HIV Agents↗
PubMed2003

Protein binding in antiretroviral therapies.

There is marked variability in the extent to which the three classes of antiretroviral (ARV) drugs bind to plasma proteins (<5 to >99%). Protease inhibitors (PIs), with the exception of indinavir, are more than 90% protein bound, mainly to alpha1-acid glycoprotein (AAG). Efavirenz, a nonnucleoside reverse transcriptase inhibitor (NNRTI), is more than 99% bound, mainly to albumin. Nucleoside reverse transcriptase inhibitors (NRTIs) are not highly protein bound. The pharmacological activity of ARV drugs is dependent on unbound drug entering cells that harbor the human immunodeficiency virus (HIV). There has been concern that changes in protein binding could impact on antiviral activity and management. However, for PIs and NNRTIs, and for many drugs given orally, altered plasma binding would not be expected to influence the average exposure to unbound (active) drug after chronic oral dosing. Nevertheless, there will be a change in the relationship between total and unbound concentrations that will be important if, as part of therapeutic drug monitoring, the total rather than the unbound drug is measured. Measuring drug concentrations that are needed to inhibit different HIV strains (wild type and drug resistant) in vitro could also cause confusion because most methods employ bovine serum in the assay medium, and unbound concentrations are not directly measured. Estimating unbound drug concentrations in human plasma and in incubation media can be highly method dependent and thus may affect the calculated IC50 (the concentration of drug that results in 50% inhibition of viral replication). Because inhibitory quotients (IQs = C(trough)/IC50) are becoming part of pharmacokinetic/pharmacodynamic (PK/PD) analyses of clinical trial data, the strengths and weaknesses of the methods used for the determination of unbound drug concentration in plasma and in vitro systems--ultracentrifugation, ultrafiltration, and equilibrium dialysis--need to be understood. Consensus on standard procedures must be reached. In June 2002, a panel of experts assembled by the Forum for Collaborative HIV Research met in Washington, DC, to review the basic principles of protein binding of ARV drugs, and to discuss the impact that changes in plasma protein binding may have on the PKs and activity of ARV drugs as well as on therapeutic drug monitoring. The purpose of the meeting was to discuss the following topics: (1) basic principles of protein binding and how changes in binding can impact on drug PKs and drug exposure in vivo, (2) variability in plasma protein binding among patients taking ARV drugs, (3) the impact of HIV infection and concomitant diseases on the extent of plasma protein binding, (4) the likelihood of clinically relevant drug interactions at the level of plasma protein binding, (5) the evidence that measuring unbound concentrations of ARV drugs in the plasma of patients gives more meaningful information than total drug concentration and, therefore, should be considered in routine therapeutic drug monitoring of ARV agents, (6) optimal method(s) for measuring the unbound concentration of drugs in vitro (for IC50 determination) and in vivo, and (7) future studies that need to be considered to fully understand the importance of plasma protein binding in therapeutic drug monitoring. This report summarizes the topics discussed at this meeting. It guides the reader through the discussions that allowed the panel to formulate a series of statements regarding the significance of plasma protein binding of ARV drugs when studied in vitro and in vivo. The roundtable participants also identified research priorities that are important for understanding the sources of inter- and intraindividual variability in protein binding in patients. These include obtaining data on unbound as well as on total concentrations in PK studies; looking at variants of AAG and whether they differ in binding affinity; and emphasizing the importance of developing a standard procedure for drug susceptibility assays used to determine IC50 values.

Animals↗