Circadian modulation of episodic bursts is recognized as the normal physiological pattern of diurnal variation in plasma cortisol levels. The primary physiological factors underlying these diurnal patterns are the ultradian timing of secretory events, circadian modulation of the amplitude of secretory events, infusion of the hormone from the adrenal gland into the plasma, and clearance of the hormone from the plasma by the liver. Each measured plasma cortisol level has an error arising from the cortisol immunoassay. We demonstrate that all of these three physiological principles can be succinctly summarized in a single stochastic differential equation plus measurement error model and show that physiologically consistent ranges of the model parameters can be determined from published reports. We summarize the model parameters in terms of the multivariate Gaussian probability density and establish the plausibility of the model with a series of simulation studies. Our framework makes possible a sensitivity analysis in which all model parameters are allowed to vary simultaneously. The model offers an approach for simultaneously representing cortisol's ultradian, circadian, and kinetic properties. Our modeling paradigm provides a framework for simulation studies and data analysis that should be readily adaptable to the analysis of other endocrine hormone systems.

The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.

SC-52151, an HIV-1 protease inhibitor, was developed as an ethanol-based elixir and subsequently as a self-emulsifying drug delivery system (SEDDS) to improve bioavailability. To evaluate formulation and treatment regimen effects, we conducted a four-arm, phase I/II study using the highest previously tested daily dose, 2250 mg. Forty-nine patients received the elixir or SEDDS at a dosage of 750 mg three times daily or 1125 mg twice daily for 14 days. One patient developed hypertriglyceridemia, and one had fever and dyspnea. The SEDDS formulation compared with the elixir resulted in a larger area under the concentration-time curve (AUC, p < 0.001), peak (Cmax, p = 0.041) and trough (Cmin, p = 0.025). Twice-daily administration compared with administration three times daily produced a higher cumulative AUC (p = 0.008). Both SEDDS regimens produced mean plasma concentrations above the 90% inhibitory concentration (IC90) for HIV. A mean decline of 0.03 log10 RNA copies (SEDDS) and an increase of 0.15 log10 (elixir) were observed. Although SC-52151 was well tolerated and the SEDDS formulation resulted in plasma concentrations above the IC90 for viral replication, no antiviral activity was produced.